Статті в журналах з теми "Minimal pharmacophores"
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1
Mortier, Jérémie, Pratik Dhakal, and Andrea Volkamer. "Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces." Molecules 23, no. 8 (August 6, 2018): 1959. http://dx.doi.org/10.3390/molecules23081959.
Анотація:
Pharmacophore models are an accurate and minimal tridimensional abstraction of intermolecular interactions between chemical structures, usually derived from a group of molecules or from a ligand-target complex. Only a limited amount of solutions exists to model comprehensive pharmacophores using the information of a particular target structure without knowledge of any binding ligand. In this work, an automated and customable tool for truly target-focused (T²F) pharmacophore modeling is introduced. Key molecular interaction fields of a macromolecular structure are calculated using the AutoGRID energy functions. The most relevant points are selected by a newly developed filtering cascade and clustered to pharmacophore features with a density-based algorithm. Using five different protein classes, the ability of this method to identify essential pharmacophore features was compared to structure-based pharmacophores derived from ligand-target interactions. This method represents an extremely valuable instrument for drug design in a situation of scarce ligand information available, but also in the case of underexplored therapeutic targets, as well as to investigate protein allosteric pockets and protein-protein interactions.
2
Petrikaite, Vilma, Eduardas Tarasevišius, and Alvydas Pavilonis. "New ethacridine derivatives as the potential antifungal and antibacterial preparations." Medicina 43, no. 8 (August 11, 2007): 657. http://dx.doi.org/10.3390/medicina43080084.
Анотація:
Until the 20th century fungal infections were rather easy cured, and the need of new antifungal drugs was low. However, low choice of antifungal preparations, their toxicity, limited spectrum of action, and ability to produce resistant strains show the need of new effective medicines for systemic fungal diseases in nowadays. Our goal of research was to synthesize new antimicrobial compounds containing three or more pharmacophores in one molecule. The initial 5-substituted-2-methylmercaptothiazolidin-4-ones were subjected to S-demethylation to yield 2- amino-substituted thiazolidinones. Ethacridine, nitrofuran aldehydes and nitrobenzene aldehyde as pharmacophoric amino or aldehyde group having compounds have been used. Antimicrobial (antifungal) activity of the new compounds was screened in vitro in these bacterial cultures: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Bacillus subtilis ATCC 6633, Klebsiella pneumoniae ATCC 33499 and fungal cultures: Candida albicans ATCC 60l93, Candida glabrata, Candida krusei, Candida kefyr ATCC 86l4, Candida tropicalis ATCC 8302, Candida parapsilosis. Results showed that the new compounds were significantly more effective as antimicrobial agents than initial preparation ethacridine. Ethacridine derivatives were not only effective against numerous gram-positive and some gram-negative bacteria, but the spectrum of action has been discovered against fungi. Minimal fungistatic concentration varies in the range l0.0–750 µg/mL and antibacterial concentration is in the range 62.5–l000 µg/mL. Compound 2a having nitrofuryl substituent in the fifth position of tiazolidine cycle was the most active of synthesized ethacridine compounds. The obtained results gave the opportunity to separate the perspective group of potential antiinfective compounds.
3
Spasov, Alexander, Irina Ovchinnikova, Olga Fedorova, Yulia Titova, Denis Babkov, Vadim Kosolapov, Alexander Borisov, et al. "Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury." Molecules 28, no. 2 (January 11, 2023): 741. http://dx.doi.org/10.3390/molecules28020741.
Анотація:
The problem of lung damage originating from excessive inflammation and cytokine release during various types of infections remains relevant and stimulates the search for highly effective and safe drugs. The biological activity of the latter may be associated with the regulation of hyperactivation of certain immune cells and enzymes. Here, we propose the design and synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines as promising double-acting pharmacophores inhibiting IL-6 and NO. The anti-inflammatory activity of 14 target compounds was studied on isolated primary murine macrophages after LPS stimulation. Seven compounds were identified to inhibit the synthesis of nitric oxide and interleukin 6 at a concentration of 100 µM. The most active compounds are micromolar inhibitors of IL-6 secretion and NO synthesis, showing a minimal impact on innate immunity, unlike the reference drug dexamethasone, along with acceptable cytotoxicity. Evaluation in an animal model of acute lung injury proved the protective activity of compound 6e, which was supported by biochemical, cytological and morphological markers.
4
Mishra, Pranjali, Muskan Srivastav, Yashveer Gautam, Monal Singh, Neeraj Verma, Deepak S. Kapkoti, Shailendra P. Singh, Anil K. Singh, and Devendra P. Rao. "A REVIEW IN CURCUMINOIDS: CHEMISTRY, ANTICANCER ACTIVITY AND FUTURE PROSPECTS." INDIAN DRUGS 61, no. 05 (May 28, 2024): 7–23. http://dx.doi.org/10.53879/id.61.05.14041.
Анотація:
ABSTRACT Curcumin is a biologically active phytochemical which manifests therapeutic activities in numerous health conditions, including cancer. Several curcuminoids obtained naturally and synthesized artificially also showcase anti-cancer and anti-tumorigenic effects. However, its water insolubility poses difficulties in its application to biological systems, lowering its availability in living tissues, which can be overcome by using various micro-encapsulation and nano-formulations of curcumin. When used in combination with other chemotherapeutic drugs, curcumin enhances the anti-carcinogen potential and reduces the side effects induced via chemotherapy. Structural modelling of basic pharmacophores of curcumin can enhance its biological and pharmacokinetic properties, as revealed by structure-activity relationship studies of curcumin. Various clinical trials of curcumin have proven its worth as an anti-neoplastic agent in humans, with minimal side effects. Its mechanism of action involves blockage of cell-signalling pathways and cellular enzymes, promotion of immunomodulatory effects and induction of programmed cell death in cancerous cells. Curcumin is an interesting molecule with diverse effects on various diseases, but its absolute potential has yet to be reached. Hence, more in-depth studies and clinical trials are needed. This review outlines curcumin’s chemical properties and summarizes its anti-cancer and pharmacokinetic potential.
5
Maatuf, Yossi, Matan Geron, and Avi Priel. "The Role of Toxins in the Pursuit for Novel Analgesics." Toxins 11, no. 2 (February 23, 2019): 131. http://dx.doi.org/10.3390/toxins11020131.
Анотація:
Chronic pain is a major medical issue which reduces the quality of life of millions and inflicts a significant burden on health authorities worldwide. Currently, management of chronic pain includes first-line pharmacological therapies that are inadequately effective, as in just a portion of patients pain relief is obtained. Furthermore, most analgesics in use produce severe or intolerable adverse effects that impose dose restrictions and reduce compliance. As the majority of analgesic agents act on the central nervous system (CNS), it is possible that blocking pain at its source by targeting nociceptors would prove more efficient with minimal CNS-related side effects. The development of such analgesics requires the identification of appropriate molecular targets and thorough understanding of their structural and functional features. To this end, plant and animal toxins can be employed as they affect ion channels with high potency and selectivity. Moreover, elucidation of the toxin-bound ion channel structure could generate pharmacophores for rational drug design while favorable safety and analgesic profiles could highlight toxins as leads or even as valuable therapeutic compounds themselves. Here, we discuss the use of plant and animal toxins in the characterization of peripherally expressed ion channels which are implicated in pain.
6
Wermelinger, Guilherme Freimann, Lucas Rubini, Anna Carolina Carvalho da Fonseca, Gabriel Ouverney, Rafael P. R. F. de Oliveira, Acácio S. de Souza, Luana S. M. Forezi, Gabriel Limaverde-Sousa, Sergio Pinheiro, and Bruno Kaufmann Robbs. "A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma." Biomedicines 11, no. 6 (June 14, 2023): 1711. http://dx.doi.org/10.3390/biomedicines11061711.
Анотація:
Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.
7
Bourne, Yves, Gerlind Sulzenbacher, Laurent Chabaud, Rómulo Aráoz, Zoran Radić, Sandrine Conrod, Palmer Taylor, Catherine Guillou, Jordi Molgó, and Pascale Marchot. "The Cyclic Imine Core Common to the Marine Macrocyclic Toxins Is Sufficient to Dictate Nicotinic Acetylcholine Receptor Antagonism." Marine Drugs 22, no. 4 (March 27, 2024): 149. http://dx.doi.org/10.3390/md22040149.
Анотація:
Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and electrophysiology experiments on nAChR subtypes and their soluble AChBP surrogates evidenced common trends for substantial antagonism, binding affinities, and receptor-subtype selectivity. Earlier, complementary crystal structures of AChBP complexes showed that common determinants within the binding nest at each subunit interface confer high-affinity toxin binding, while distinctive determinants from the flexible loop C, and either capping the nest or extending toward peripheral subsites, dictate broad versus narrow receptor subtype selectivity. From these data, small spiroimine enantiomers mimicking the functional core motif of phycotoxins were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChR subtypes revealed preserved antagonism for both enantiomers, despite lower subtype specificity and binding affinities associated with faster reversibility compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to modest affinities and positional variability of the spiroimines, along with a range of AChBP loop-C conformations denoting a prevalence of antagonistic properties. These data highlight the major contribution of the spiroimine core to binding within the nAChR nest and confirm the need for an extended interaction network as established by the macrocyclic toxins to define high affinities and marked subtype specificity. This study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new antagonists targeting disease-associated nAChR subtypes.
8
Caldas Lopes, Eloisi, Shieh Jae-Hung, Srikanth Ambati, Su Tsann-Long, Fabian Correa, Elizabeth Peguero, and Malcolm A. S. Moore. "Novel Alkylating Agent, Ureidomustine Exhibit Pre-Clinical Efficacy in B-Cell Lymphoma with Minimal Dose-Limiting Myelotoxicity." Blood 126, no. 23 (December 3, 2015): 1556. http://dx.doi.org/10.1182/blood.v126.23.1556.1556.
Анотація:
Abstract Many patients with B-cell lymphomas, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), are not cured by conventional chemo-immunotherapy. One reason for this is because these drugs, while effective, are limited by their narrow therapeutic window and significant toxicities. B-cell lymphomas are highly dependent on DNA damage checkpoints, and hence are biologically responsive to drugs that trigger these checkpoints. Hence, In order to identify superior DNA damaging anti-lymphoma drugs we evaluated a series of novel, third generation, DNA-directed alkylating agents that have DNA specific binding domains chemically linked via urea, carbamate or hydrazinecarboxamide to N-mustard pharmacophores. The chemically favorable water-soluble ureidomustine (BO-1055) was evaluated for activity against 23 human lymphoma cell lines including MCL, DLBCL (GCB and ABC subtype) and a spontaneous murine B-cell lymphoma. Fifty % of these MCL and DLBCL cell lines exhibited BO-1055 IC50 values in the nanomolar range including even markedly chemo-resistant cell lines as OCI-Ly10 (IC50 0.117μM ±0.21). In marked contrast, against normal human tissues (lung fibroblast IMR90, kidney fibroblast CV1, mesenchymal stromal, bronchial epithelium, myofibroblast, bone marrow-derived endothelium) and hematopoietic cells (cord blood CD34+ cells, colony-forming assay for hematopoietic progenitors) and in cobblestone area-forming assay for hematopoietic stem cells, BO-1055 IC50s were > 10μM. Hence BO-1055 has a significant therapeutic window (50-100-fold) between its toxicity against B-cell lymphomas compared to normal human cells. We evaluated BO-1055 cardiotoxicity in the HL-1 cardiomyocyte line and observed a 227-fold less cytotoxicity compared to Doxorubicin. Drug combination studies with BO-1055 and an Hsp90 inhibitor (PU-H71), an Hsp70 inhibitor (TT46), doxorubicin and bortezomib (Velcade) demonstrated synergistic effects based on Compusyn analysis with very low combination indices in 50% of lymphoma cell lines. The synergistic effect was not observed in normal cells. Notably, BO-1055 caused downregulation of the critical lymphoma oncoproteins MYC and BCL6, but not Bcl2. BCL6 normally suppresses the ATR-driven S-phase checkpoint. Accordingly treatment with BO-1055 resulted in accumulation of cells in S-phase and up-regulation of proteins involved in DNA repair and intra-S-phase checkpoints [MRE11, p-P95/NBS1 (ser343), RAD50, p-ATR (ser428)]. Finally, xenograft experiments in NSG mice bearing MCL JEKO1 GFP/luciferase+ tumors treated with BO-1055 (30mg/kg) 3x/week showed complete tumor remission after 2 weeks of treatment as monitored by luminescent imaging. In summary, BO-1055 is emerging as a potent therapeutic agent for B-cell lymphomas, with little toxicity against normal tissues and hence potentially wider therapeutic window than current lymphoma drugs. Disclosures Caldas Lopes: BOtique Biopharm: Employment.
9
Vawhal, Pallavi Kishor, Shailaja B. Jadhav, Sumit Kaushik, Kahnu Charan Panigrahi, Chandan Nayak, Humaira Urmee, Sharuk L. Khan, et al. "Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay." Molecules 28, no. 3 (January 19, 2023): 1004. http://dx.doi.org/10.3390/molecules28031004.
Анотація:
Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.
10
Robertson, Gregory T., Eric J. Bonventre, Timothy B. Doyle, Qun Du, Leonard Duncan, Timothy W. Morris, Eric D. Roche, Dalai Yan, and A. Simon Lynch. "In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Microbiology Profiling Studies with Staphylococci and Streptococci." Antimicrobial Agents and Chemotherapy 52, no. 7 (July 2008): 2324–34. http://dx.doi.org/10.1128/aac.01651-07.
Анотація:
ABSTRACT We present data from antimicrobial assays performed in vitro that pertain to the potential clinical utility of a novel rifamycin-quinolone hybrid antibiotic, CBR-2092, for the treatment of infections mediated by gram-positive cocci. The MIC90s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 μg/ml. Against Staphylococcus aureus, CBR-2092 exhibited prolonged postantibiotic effects (PAEs) and sub-MIC effects (SMEs), with values of 3.2, 6.5, and >8.5 h determined for the PAE (3× MIC), SME (0.12× MIC), and PAE-SME (3× MIC/0.12× MIC) periods, respectively. Studies of genetically defined mutants of S. aureus indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In minimal bactericidal concentration and time-kill studies, CBR-2092 exhibited bactericidal activity against staphylococci that was retained against rifampin- or intermediate quinolone-resistant strains, with apparent paradoxical cidal characteristics against rifampin-resistant strains. In spontaneous resistance studies, CBR-2092 exhibited activity consistent with balanced contributions from its composite pharmacophores, with a mutant prevention concentration of 0.12 μg/ml and a resistance frequency of <10−12 determined at 1 μg/ml in agar for S. aureus. Similarly, CBR-2092 suppressed the emergence of preexisting rifamycin resistance in time-kill studies undertaken at a high cell density. In studies of the intracellular killing of S. aureus, CBR-2092 exhibited prolonged bactericidal activity that was superior to the activities of moxifloxacin, rifampin, and a cocktail of moxifloxacin and rifampin. Overall, CBR-2092 exhibited promising activity in a range of antimicrobial assays performed in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.
11
Cheng, Jeffrey, Enming Xing, Shabber Mohammed, Emma Montgomery, Lauren Granchie, Christopher Coss, and Pui-Kai Li. "Abstract 3106: Design, synthesis, and screening of niclosamide analogs as androgen receptor degraders for hepatocellular carcinoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3106. http://dx.doi.org/10.1158/1538-7445.am2023-3106.
Анотація:
Abstract Hepatocellular Carcinoma (HCC) is the leading form of liver cancer, the 6th most common type, and the 4th leading cause of cancer death worldwide. Interestingly, HCC occurs two to four times more in males than females. A possible explanation for this sexual dimorphism is the implication of androgen and the Androgen Receptor (AR). However, previous clinical trials among HCC patients have shown no significant survival benefit after the administration of antiandrogen drugs (e.g. Enzalutamide) that block the Ligand-Binding Domain (LBD) of the Full-length Androgen Receptor (AR-FL). Instead, our lab has developed a novel approach using small molecular analogs of the previously FDA-approved drug, Niclosamide, to degrade full-length AR and its spliced variants within HCC cell lines. The primary goal of this project was to evaluate the minimal necessary pharmacophores for the biological activity of the Niclosamide scaffold. To do so, 23 analogs were synthesized and tested on three different HCC cell lines (SNU 475, 423, and LM3) using a CCK8 cell viability assay. Preliminary results have shown that only Niclosamide analogs with i.) electron-withdrawing groups on the aniline ring; ii) a conserved hydroxy group on the salicylic ring, and iii) a free amide group in the middle have cytotoxic activity. Further work will be completed using western blot to determine if there’s any correlation between androgen receptor degradation and in vitro potency. In conclusion, Niclosamide analogs have indicated promising potential to inhibit HCC cell lines by targeting the Androgen Receptor. Citation Format: Jeffrey Cheng, Enming Xing, Shabber Mohammed, Emma Montgomery, Lauren Granchie, Christopher Coss, Pui-Kai Li. Design, synthesis, and screening of niclosamide analogs as androgen receptor degraders for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3106.
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Alhadrami, Hani A., Ahmed M. Sayed, Heba Al-Khatabi, Nabil A. Alhakamy та Mostafa E. Rateb. "Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 MPro Inhibitor". Pharmaceuticals 14, № 6 (5 червня 2021): 541. http://dx.doi.org/10.3390/ph14060541.
Анотація:
The COVID-19 pandemic is still active around the globe despite the newly introduced vaccines. Hence, finding effective medications or repurposing available ones could offer great help during this serious situation. During our anti-COVID-19 investigation of microbial natural products (MNPs), we came across α-rubromycin, an antibiotic derived from Streptomyces collinus ATCC19743, which was able to suppress the catalytic activity (IC50 = 5.4 µM and Ki = 3.22 µM) of one of the viral key enzymes (i.e., MPro). However, it showed high cytotoxicity toward normal human fibroblasts (CC50 = 16.7 µM). To reduce the cytotoxicity of this microbial metabolite, we utilized a number of in silico tools (ensemble docking, molecular dynamics simulation, binding free energy calculation) to propose a novel scaffold having the main pharmacophoric features to inhibit MPro with better drug-like properties and reduced/minimal toxicity. Nevertheless, reaching this novel scaffold synthetically is a time-consuming process, particularly at this critical time. Instead, this scaffold was used as a template to explore similar molecules among the FDA-approved medications that share its main pharmacophoric features with the aid of pharmacophore-based virtual screening software. As a result, cromoglicic acid (aka cromolyn) was found to be the best hit, which, upon in vitro MPro testing, was 4.5 times more potent (IC50 = 1.1 µM and Ki = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC50 > 100 µM). This report highlights the potential of MNPs in providing unprecedented scaffolds with a wide range of therapeutic efficacy. It also revealed the importance of cheminformatics tools in speeding up the drug discovery process, which is extremely important in such a critical situation.
13
Osborne, Joseph, Naveed Hassan Akhtar, Shankar Vallabhajosula, Anastasia Nikolopoulou, Kevin P. Maresca, Shawn M. Hillier, John L. Joyal, et al. "Tc-99m labeled small-molecule inhibitors of prostate-specific membrane antigen (PSMA): New molecular imaging probes to detect metastatic prostate adenocarcinoma (PC)." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 173. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.173.
Анотація:
173 Background: Sensitive and specific imaging remains a clinically-relevant problem for men with PC. PSMA is a well established target for imaging of PC with therapeutic implications. We have recently developed novel 99mTc-labeled small molecule inhibitors of the enzymatic domain of PSMA based on glutamate-urea-glutamate and glutamate-urea-lysine pharmacophores, and contain a bis-imidazole chelator to complex Tc-99m. Preclinical studies with PSMA positive LNCaP cells and xenografts demonstrate that 99mTc-MIP-1404 and 99mTc-MIP-1405 bind to PSMA with high affinity and localize in tumors rapidly. This study reports the first human data in men with metastatic PC and in healthy male subjects. Methods: Under an exploratory IND, using a cross-over design, the pharmacokinetics, biodistribution, and tumor uptake of 99mTc-MIP-1404 and 99mTc-MIP-1405 were compared in 6 healthy men and 6 men with radiographic evidence of metastatic PC. Whole body images were obtained at 10 min, 1, 2, 4 and 24 hr. Single photon emission computed tomography (SPECT) was performed between 3–4 hours post injection. Results: Both agents cleared the blood rapidly with MIP-1404 demonstrating significantly lower urinary activity (7%) compared to MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal and parotid glands. Uptake in liver and kidney was acceptable for imaging at 1-2 hr post injection (PI). In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 hr PI. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone and CT scans, In majority of patients, more lesions including sub-cm lymph nodes were seen with 99mTc-MIP-1404 and 99mTc-MIP-1405. The high contrast images exhibited signal:noise ratios from 3:1 to 28:1 at 4 and 24 hr. Conclusions: 99mTc-MIP-1404 and 99mTc-MIP-1405 identified a greater number of lesions than bone scans and rapidly detected soft tissue PC lesions including sub-cm lymph nodes. Since 99mTc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high risk clinically-localized PC.
14
Hall, Ronald G., Jotam Pasipanodya, William C. Putnam, John Griswold, Sharmila Dissanaike, Raja Reddy Kallem, Vindhya Edpuganti, and Indhumathy Subramaniyan. "1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S670—S671. http://dx.doi.org/10.1093/ofid/ofaa439.1501.
Анотація:
Abstract Background Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. Methods A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. Results The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities Summary of pharmacokinetic parameters Conclusion C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. Disclosures Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)
15
Schlitzer, Martin, Labaniel Rodriguez, and Peter F. Kador. "Synthesis of potential aldose reductase inhibitors based on minimal pharmacophore requirements." Journal of Pharmacy and Pharmacology 53, no. 6 (June 2001): 831–39. http://dx.doi.org/10.1211/0022357011776180.
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Papke, Roger L., Kinga Chojnacka та Nicole A. Horenstein. "The Minimal Pharmacophore for Silent Agonism of the α7 Nicotinic Acetylcholine Receptor". Journal of Pharmacology and Experimental Therapeutics 350, № 3 (2 липня 2014): 665–80. http://dx.doi.org/10.1124/jpet.114.215236.
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Magnin, David R., Prakash C. Taunk, James G. Robertson, Aiying Wang, Jovita Marcinkeviciene, Mark S. Kirby, and Lawrence G. Hamann. "Seco-prolinenitrile inhibitors of dipeptidyl peptidase IV define minimal pharmacophore requirements at P1." Bioorganic & Medicinal Chemistry Letters 16, no. 6 (March 2006): 1731–34. http://dx.doi.org/10.1016/j.bmcl.2005.11.098.
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Johnston, Alexis, and Adegboyega K. Oyelere. "Abstract 4492: Deferiprone optimization for the treatment of triple-negative breast cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4492. http://dx.doi.org/10.1158/1538-7445.am2024-4492.
Анотація:
Abstract Triple-negative breast cancer (TNBC) is the leading cause of new cancer cases and the second leading cause of cancer deaths in American women disproportionately affecting Black and Hispanic women under 40. Currently, there is no targeted therapy for TNBC and treatment options to manage this lethal disease include surgery, adjuvant chemotherapy and radiotherapy. Among the chemotherapy agents, combination of the PARP inhibitors with DNA-damaging results in a more promising anti-tumor effect. A better understanding of TNBC etiology has aided in unraveling the roles of two additional cellular targets - androgen receptor (AR) and histone lysine demethylase (KDM) - in the viability and survival of TNBC. Interestingly, AR overexpression is the most important driver of prostate cancer (PCa). A class of current medications used to treat PCa act as androgen receptor (AR) antagonists (or antiandrogens). Antiandrogens are under investigation in the clinic as potential therapies for luminal AR (LAR) subtypes of TNBC, a particularly worrisome subtype that frequently metastasizes to regional lymph nodes and bones. Although LAR TNBC constitutes 15-20% of TNBCs, it is characterized by minimal response to chemotherapy and aggressiveness. It is therefore plausible to repurpose and optimize antiandrogens, in the context of designed multiple ligands; to obtain a TNBC-targeting therapy effective against several subtypes of this heterogenous disease, including the basal subtype that is responsible for ~80% of TNBC incidence. The proposed therapeutics are dual-acting antiandrogen-KDM inhibitors. The antiandrogen moiety of these agents will enable TNBC cell-targeting and translocation of the drug into the nucleus where inhibition of KDM will prevent transcription of KDMs that promote tumor growth. The three pharmacophores of these agents are (i) an AR binding group, (ii) a linker, and (iii) an iron-binding group. Two functional classes of these compounds, alkyl- and aryl-derivatives, vary in the design of the AR binding moiety. To optimize these agents, the methylene linker length is varied in each class for in vitro determination of the optimal length for increased drug efficacy. The compounds are tested on TNBC cell lines (MDA-MB-231, low AR+; and MDA-MB-453, high AR+), and ER+ BCa (MCF-7) while PCa cell lines (LNCaP PCa, AR+; and DU 145, PCa, AR-) serve as controls for AR dependency of the compounds. Longer linker length compounds exhibited low micromolar cytotoxicity and selectivity for AR+ TNBC and PCa cell lines. Further analysis of lead compounds in TNBC cells aided in understanding the effects on targets, transcriptomic effects via RNA sequencing analysis and the mechanism of action. Thus far, the designed dual-acting therapeutics have potential to revolutionize the design of anticancer drugs and improve treatment outcome for TNBC patients. Citation Format: Alexis Johnston, Adegboyega K. Oyelere. Deferiprone optimization for the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4492.
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Cruz, María del Carmen, María Salazar, Yésica Garciafigueroa, Dolores Hernández, Francisco Díaz, Germán Chamorro та Joaquín Tamariz. "Hypolipidemic Activity of New Phenoxyacetic Derivatives Related to α-Asarone with Minimal Pharmacophore Features". Drug Development Research 60, № 3 (3 жовтня 2003): 186–95. http://dx.doi.org/10.1002/ddr.10281.
20
Bjij, Imane, Pritika Ramharack, Shama Khan, Driss Cherqaoui, and Mahmoud E. S. Soliman. "Tracing Potential Covalent Inhibitors of an E3 Ubiquitin Ligase through Target-Focused Modelling." Molecules 24, no. 17 (August 28, 2019): 3125. http://dx.doi.org/10.3390/molecules24173125.
Анотація:
The Nedd4-1 E3 Ubiquitin ligase has been implicated in multiple disease conditions due its overexpression. Although the enzyme may be targeted both covalently and non-covalently, minimal studies provide effective inhibitors against it. Recently, research has focused on covalent inhibitors based on their characteristic, highly-selective warheads and ability to prevent drug resistance. This prompted us to screen for new covalent inhibitors of Nedd4-1 using a combination of computational approaches. However, this task proved challenging due to the limited number of electrophilic moieties available in virtual libraries. Therefore, we opted to divide an existing covalent Nedd4-1 inhibitor into two parts: a non-covalent binding group and a pre-selected α, β-unsaturated ester that forms the covalent linkage with the protein. A non-covalent pharmacophore model was built based on molecular interactions at the binding site. The pharmacophore was then subjected to virtual screening to identify structurally similar hit compounds. Multiple filtrations were implemented prior to selecting four hits, which were validated with a covalent conjugation and later assessed by molecular dynamic simulations. The results showed that, of the four hit molecules, Zinc00937975 exhibited advantageous molecular groups, allowing for favourable interactions with one of the characteristic cysteine residues. Predictive pharmacokinetic analysis further justified the compound as a potential lead molecule, prompting its recommendation for confirmatory biological evaluation. Our inhouse, refined, pharmacophore model approach serves as a robust method that will encourage screening for novel covalent inhibitors in drug discovery.
21
Wood, Daniel J., J. Daniel Lopez-Fernandez, Leanne E. Knight, Islam Al-Khawaldeh, Conghao Gai, Shengying Lin, Mathew P. Martin, et al. "FragLites—Minimal, Halogenated Fragments Displaying Pharmacophore Doublets. An Efficient Approach to Druggability Assessment and Hit Generation." Journal of Medicinal Chemistry 62, no. 7 (March 12, 2019): 3741–52. http://dx.doi.org/10.1021/acs.jmedchem.9b00304.
22
Ostash, Bohdan, Emma Doud, and Victor Fedorenko. "The molecular biology of moenomycins: towards novel antibiotics based on inhibition of bacterial peptidoglycan glycosyltransferases." Biological Chemistry 391, no. 5 (May 1, 2010): 499–504. http://dx.doi.org/10.1515/bc.2010.053.
Анотація:
AbstractMoenomycins are phosphoglycolipid antibiotics and the only known natural product inhibitors of peptidoglycan glycosytransferases (PGTs). Techniques that would allow facile diversification of the moenomycin structure would facilitate the development of novel antibiotics, which are urgently needed in the wake of multidrug resistant bacterial infections. The cloning and initial characterization of the moenomycin biosynthetic genes has already redefined the minimal moenomycin pharmacophore and now opens the door for the biocombinatorial generation of bioactive moenomycin fragments. Here, we highlight the importance of research on the genetic mechanisms that regulate moenomycin biosynthesis and that confer moenomycin resistance to bacteria in the development of novel anti-infectives based on PGT inhibition.
23
Gozalbes, Rafael, Silvia Mosulén, Rodrigo J. Carbajo, and Antonio Pineda-Lucena. "Development and NMR validation of minimal pharmacophore hypotheses for the generation of fragment libraries enriched in heparanase inhibitors." Journal of Computer-Aided Molecular Design 23, no. 8 (May 7, 2009): 555–69. http://dx.doi.org/10.1007/s10822-009-9269-0.
24
Ladouceur, Gaétan, Dale E. Mais, Joseph A. Jakubowski, Barbara G. Utterback, and David W. Robertson. "Structural homologies among thromboxane (TXA2) receptor antagonists: Minimal pharmacophoric requirements for high affinity interaction with TXA2 receptors." Bioorganic & Medicinal Chemistry Letters 1, no. 3 (January 1991): 173–78. http://dx.doi.org/10.1016/s0960-894x(01)80794-0.
25
Mittal, Ravi K., and Priyank Purohit. "Quinoline-3-carboxylate Derivatives: A New Hope as an Antiproliferative Agent." Anti-Cancer Agents in Medicinal Chemistry 20, no. 16 (November 5, 2020): 1981–91. http://dx.doi.org/10.2174/1871520620666200619175906.
Анотація:
Background: The quinoline scaffold has been an attraction due to its pharmacological activities such as anti-HIV, anti-neoplastic, anti-asthmatic, anti-tuberculotic, anti-fungal, and anti-bacterial. Objective: The designed quinoline-3-carboxylate derivatives were synthesized through a two-step reaction and evaluated for antiproliferative activity against MCF-7 and K562 cell lines. Methods: Synthesized compounds were characterized by modern analytical techniques like NMR, 2DNMR, mass, and IR. Moreover, the purity of compounds was analyzed through the HPLC. In the progress of biological results, all synthesized compounds were evaluated for antiproliferative activity against MCF-7 and K562 cell lines. Results: The synthesized compounds exhibited micromolar inhibition in all over the ranges, however, some of the compounds showed better activity than the standard anticancer drug such, as 4m and 4n with the IC50 value of 0.33μM against the MCF-7 cell line, and the compounds 4k and 4m showed potential activity against the K562 cell line with the IC50 value of 0.28μM. The anti-cancer activities of compounds were found to be through the up-regulation of intrinsic apoptosis pathways. Conclusion: The biological data of all compounds in both cell lines were utilized for the structural activity relationship of the quinoline-3-carboxylate pharmacophore. The active lead was further validated through rigorous in silico studies for the drug-likeness (QED) and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Here in the present research is utilized for the demonstration of an important pharmacophore, which could be utilized for further development to become a lead as an anticancer agent with minimal toxicity.
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Khomutov, Maxim A., Fabio Giovannercole, Laura Onillon, Marija V. Demiankova, Byazilya F. Vasilieva, Arthur I. Salikhov, Sergey N. Kochetkov, Olga V. Efremenkova, Alex R. Khomutov, and Daniela De Biase. "A Desmethylphosphinothricin Dipeptide Derivative Effectively Inhibits Escherichia coli and Bacillus subtilis Growth." Biomolecules 13, no. 10 (September 26, 2023): 1451. http://dx.doi.org/10.3390/biom13101451.
Анотація:
New antibiotics are unquestionably needed to fight the emergence and spread of multidrug-resistant bacteria. To date, antibiotics targeting bacterial central metabolism have been poorly investigated. By determining the minimal inhibitory concentration (MIC) of desmethylphosphinothricin (Glu-γ-PH), an analogue of glutamate with a phosphinic moiety replacing the γ-carboxyl group, we previously showed its promising antibacterial activity on Escherichia coli. Herein, we synthetized and determined the growth inhibition exerted on E. coli by an L-Leu dipeptide derivative of Glu-γ-PH (L-Leu-D,L-Glu-γ-PH). Furthermore, we compared the growth inhibition obtained with this dipeptide with that exerted by the free amino acid, i.e., Glu-γ-PH, and by their phosphonic and non-desmethylated analogues. All the tested compounds were more effective when assayed in a chemically-defined minimal medium. The dipeptide L-Leu-D,L-Glu-γ-PH had a significantly improved antibacterial activity (2 μg/mL), at a concentration between the non-desmethytaled (0.1 μg/mL) and the phosphonic (80 μg/mL) analogues. Also, in Bacillus subtilis, the dipeptide L-Leu-D,L-Glu-γ-PH displayed an activity comparable to that of the antibiotic amoxicillin. This work highlights the antibacterial relevance of the phosphinic pharmacophore and proposes new avenues for the development of novel antimicrobial drugs containing the phosphinic moiety.
27
Demeter, David A., Herschel J. R. Weintraub, and James J. Knittel. "The Local Minima Method (LMM) of Pharmacophore Determination: A Protocol for Predicting the Bioactive Conformation of Small, Conformationally Flexible Molecules." Journal of Chemical Information and Computer Sciences 38, no. 6 (November 1998): 1125–36. http://dx.doi.org/10.1021/ci980404z.
28
Ji, Haitao, Benjamin Z. Stanton, Jotaro Igarashi, Huiying Li, Pavel Martásek, Linda J. Roman, Thomas L. Poulos, and Richard B. Silverman. "Minimal Pharmacophoric Elements and Fragment Hopping, an Approach Directed at Molecular Diversity and Isozyme Selectivity. Design of Selective Neuronal Nitric Oxide Synthase Inhibitors." Journal of the American Chemical Society 130, no. 12 (March 2008): 3900–3914. http://dx.doi.org/10.1021/ja0772041.
29
Rasaeifar, Bahareh, Patricia Gomez-Gutierrez, and Juan J. Perez. "New Insights into the Stereochemical Requirements of the Bombesin BB1 Receptor Antagonists Binding." Pharmaceuticals 13, no. 8 (August 17, 2020): 197. http://dx.doi.org/10.3390/ph13080197.
Анотація:
Members of the family of bombesinlike peptides exert a wide range of biological activities both at the central nervous system and in peripheral tissues through at least three G-Protein Coupled Receptors: BB1, BB2 and BB3. Despite the number of peptide ligands already described, only a few small molecule binders have been disclosed so far, hampering a deeper understanding of their pharmacology. In order to have a deeper understanding of the stereochemical features characterizing binding to the BB1 receptor, we performed the molecular modeling study consisting of the construction of a 3D model of the receptor by homology modeling followed by a docking study of the peptoids PD168368 and PD176252 onto it. Analysis of the complexes permitted us to propose prospective bound conformations of the compounds, consistent with the experimental information available. Subsequently, we defined a pharmacophore describing minimal stereochemical requirements for binding to the BB1 receptor that was used in silico screening. This exercise yielded a set of small molecules that were purchased and tested, showing affinity to the BB1 but not to the BB2 receptor. These molecules exhibit scaffolds of diverse chemical families that can be used as a starting point for the development of novel BB1 antagonists.
30
Martinenghi, Laura Daniela, Rie Jønsson, Torben Lund, and Håvard Jenssen. "Isolation, Purification, and Antimicrobial Characterization of Cannabidiolic Acid and Cannabidiol from Cannabis sativa L." Biomolecules 10, no. 6 (June 12, 2020): 900. http://dx.doi.org/10.3390/biom10060900.
Анотація:
The emergence of multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) causes a major threat to public health due to its limited therapeutic options. There is an urgent need for the development of new effective antimicrobial agents and alternative strategies that are effective against resistant bacteria. The parallel legalization of cannabis and its products has fueled research into its many therapeutic avenues in many countries around the world. This study aimed at the development of a reliable method for the extraction, purification, characterization, and quantification of cannabidiolic acid (CBDA) and its decarboxylated form cannabidiol (CBD) present in the fiber type Cannabis sativa L. The two compounds were extracted by ethanol, purified on a C18 sep-pack column, and the extracts were analyzed by high performance liquid chromatography coupled with ultraviolet (UV)–vis and ESI-MS (electrospray ionization mass spectrometry) detection. The antimicrobial effect of CBDA and CBD was also evaluated. CBD displayed a substantial inhibitory effect on Gram-positive bacteria with minimal inhibitory concentrations ranging from 1 to 2 µg/mL. Time kill analysis and minimal bactericidal concentration revealed potential bactericidal activity of CBDA and CBD. While cannabinoids showed a significant antimicrobial effect on the Gram-positive S. aureus and Staphylococcus epidermidis, no activity was noticed on Gram-negative Escherichia coli and Pseudomonas aeruginosa. CBDA presented a two-fold lower antimicrobial activity than its decarboxylated form, suggesting that the antimicrobial pharmacophore of the analyzed cannabinoids falls in the ability for permeabilizing the bacterial cell membrane and acting as a detergent-like agent. A synergy test performed on MRSA with CBD and a range of antibiotics did not indicate a synergetic effect, but noteworthy no antagonist influence either. CBD and CBDA manifested low hemolytic activity on human red blood cells. Likewise, the safety of CBD toward human keratinocyte cells presents no toxicity at a concentration of up to seven-fold higher than the antibacterial minimal inhibitory concentration. Similarly, both CBD and CBDA are well tolerated by mammals, including humans, and conserve a safe value limits for blood-contacting drug development. Overall, CBD exhibited a strong antimicrobial effect against Gram-positive strains and could serve as an alternative drug for tackling MRSA.
31
Ezekiel, Olugbogi A., Arobadade A. Oluwaotbiloba, Balogun A. Samuel, Adelakun G. Oluwatosin, Maduike N. Mary, Fadeju T. Rasheedat, Kayode O. Yetunde, et al. "Application of In-silico Methodologies in Exploring the Antagonistic Potential of Trigonella frenum-graecum on Cyclooxygenase-2 (Cox-2) in Cancer Treatment." IPS Journal of Molecular Docking Simulations 2, no. 1 (September 15, 2023): 26–36. http://dx.doi.org/10.54117/ijmds.v2i1.20.
Анотація:
Cancer is a disease in which abnormal cells divide uncontrollably and destroy body tissue. This research is dispensed utilizing in-silico drug design. Cyclooxygenase-2 (Cox-2) has been used as a target protein of the molecular docking study and fenugreek phytoconstituents obtained from PubChem were docked against Cox-2’s pocket (PDB ID: 5IKV). We used Maestro 12.8 and the Schrödinger Suite to conduct computer-based drug testing. To document compounds with the best inhibitory ability to act as cyclooxygenase antagonists in the treatment of cancer. Sixty (60) compounds described with fenugreek were docked to the active site of Cox-2 (5IKV). The results demonstrated that tricin to 2,5-dimethyl pyrazine, which are the best molecules docked at the active site of Cox-2, had -11.007 to -4.58 kcal/mol and an MM-GBSA score ranging from -31.06 to -24.52 respectively, which suggests the free binding energy posed competitive binding energy when compared to the co-crystallized ligand, 2-[[3-(Trifluoromethyl) Phenyl] Amino] Benzoic Acid. Numerous drugs have been made available, but due to their common side effects, researchers are now searching for novel herbal plants that can be utilized as long-term treatments with minimal adverse effects. Thus, utilizing computational studies such as molecular docking, MM-GBSA, pharmacophore modeling, and the lead compounds’ ADMETox characteristics were computed.
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Zapata-Acevedo, César A., and Paul L. A. Popelier. "The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study." Pharmaceuticals 15, no. 10 (October 8, 2022): 1237. http://dx.doi.org/10.3390/ph15101237.
Анотація:
The interaction of the thumb site II of the NS5B protein of hepatitis C virus and a pair of drug candidates was studied using a topological energy decomposition method called interacting quantum atoms (IQA). The atomic energies were then processed by the relative energy gradient (REG) method, which extracts chemical insight by computation based on minimal assumptions. REG reveals the most important IQA energy contributions, by atom and energy type (electrostatics, sterics, and exchange–correlation), that are responsible for the behaviour of the whole system, systematically from a short-range ligand–pocket interaction until a distance of approximately 22 Å. The degree of covalency in various key interatomic interactions can be quantified. No exchange–correlation contribution is responsible for the changes in the energy profile of both pocket–ligand systems investigated in the ligand–pocket distances equal to or greater than that of the global minimum. Regarding the hydrogen bonds in the system, a “neighbour effect” was observed thanks to the REG method, which states that a carbon atom would rather not have its covalent neighbour oxygen form a hydrogen bond. The combination of IQA and REG enables the automatic identification of the pharmacophore in the ligands. The coarser Interacting Quantum Fragments (IQF) enables the determination of which amino acids of the pocket contribute most to the binding and the type of energy of said binding. This work is an example of the contribution topological energy decomposition methods can make to fragment-based drug design.
33
Ma’arif, Burhan, Faisal Akhmal Muslikh, Luqman Alfani Najib, Ria Ramadhani Dwi Atmaja, and Meilina Ratna Dianti. "In Silico Antiosteoporosis Activity of 96% Ethanol Extract of Chrysophyllum cainito L. Leaves." Proceedings of International Pharmacy Ulul Albab Conference and Seminar (PLANAR) 1 (December 5, 2021): 61. http://dx.doi.org/10.18860/planar.v1i0.1460.
Анотація:
Estrogen deficiency causes various health problems in postmenopausal women, including osteoporosis. Phytoestrogens are emerging as potential estrogen alternatives with minimal side effects. This study aimed to predict the antiosteoporosis activity of the compounds from 96% ethanol extract of Chyrsophyllum cainito L. leaves through in silico study on 3OLS protein, an X-ray protein of ERβ. In silico analysis was carried out on the compounds from metabolite profiling results of 96% ethanol extract of C. cainito leaves from previous studies. The structure of compounds resulting from metabolite profiling of 96% ethanol extract of C. cainito leaves was made using Avogadro 1.0.1 software, geometry optimization with Chemdraw molecular docking was carried out using PyRx 0.8 software, and Biovia Discovery Studio Visualizer 2021 software was used to visualize the structure of compounds against 3OLS proteins. The physicochemical characteristics of the compounds were analyzed using the SwissADME webtool. From the result, it was known that there were seven compounds in the leaves of C. cainito, which were suspected to be phytoestrogens that had ERβ agonist properties against 3OLS protein. It was an ERβ agonist because the compound had similar parameters to 17β-estradiol in its interaction with the 3OLS protein, which had a pharmacophore distance of about 10,862, and bound to the amino acids His 475 and Glu 305 or Arg 346. The 96% ethanol extract of C. cainito leaves contained seven compounds thought to be phytoestrogen with an ERβ agonist that handled its antiosteoporosis activity.
34
Motsilanyane, Andrew Rabontsi, Zimbili Mkhize, and Sphelele Sosibo. "Computational Studies for Selected Medicinal Plants against Dolutegravir using Ligand Based Pharmacophore, Molecular Docking, ADMET Predictionsand Molecular Dynamics Simulation." Pakistan Journal of Medical and Health Sciences 16, no. 1 (January 30, 2022): 927–36. http://dx.doi.org/10.53350/pjmhs22161927.
Анотація:
Human immunodeficiency virus type 1 (HIV-1) is the causative agent for acquired immunodeficiency syndrome (AIDS). In 2020, South Africa recorded an estimated 8,2 million people living with HIV. This extensive figure is a red flag to the country, as it causes serious economic burden to its health care system. In the quest for finding a suitable inhibitor for HIV-1 protease, computer aided drug design (CADD) approachstands out to be one of the leading fields of study in pursuit of a new drug for HIV. The Lipinski rule of five was applied in screening the ninety-two plant extracts from Ocium santum, Carica papaya, Persea Americana, Azadirachta indica and Spondias mombin medicinal plants, and forty-six of the compounds complied with this rule. Afterwards, a ligand-based pharmacophore was constructed based on the active properties of the three (3) best binding compound obtained from the screened ZINC compounds (Zinc_001456687980, Zinc_001445792073 and Zinc_001461099137). Then the compounds with less than 0.5 RMSD were picked out. The best 10 compounds were docked and compared with a drug that is already in the market, dolutegravir. 3, 5-di-O-galloyl-4- O-digalloylquinic acid 3,5,4,4-Tetragqa (-8.6), epicatechin (-8) and quercitrin (-8) obtained the highest binding affinity.Even though Tetragqa had the highest binding affinity, it failing the test because of its large molecular weight. The safety evaluation and other chemical parameters that included the lipophilicity, physicochemical other properties of these compounds was performed through SwissADME/T web server. On the best top three binding compounds, only epicatechin (-8) had promising features of a drug candidate. However, the remaining compounds from the best 10 compounds were also analysed using the SwissADME/T tools, whereby two of them (juglanin and catechin) satisfied the ADMET prediction analysis. Catechin showed some promising features as well after it displayed good druglike properties, suitable for a novel compound. Lastly, molecular dynamics simulation was then performed on the three lead compounds namely; epicatechin, juglanin andcatechin against dolutegravir. The ligand protein interaction between catechin and the protein displayed minimal shift of the protein during the simulation that was performed over 100ns, signifying a strong complex association.
35
Francesconi, Valeria, Elena Cichero, Evgeny V. Kanov, Erik Laurini, Sabrina Pricl, Raul R. Gainetdinov, and Michele Tonelli. "Novel 1-Amidino-4-Phenylpiperazines as Potent Agonists at Human TAAR1 Receptor: Rational Design, Synthesis, Biological Evaluation and Molecular Docking Studies." Pharmaceuticals 13, no. 11 (November 14, 2020): 391. http://dx.doi.org/10.3390/ph13110391.
Анотація:
Targeting trace amine-associated receptor 1 (TAAR1) receptor continues to offer an intriguing opportunity to develop innovative therapies in different pharmacological settings. Pursuing our endeavors in the search for effective and safe human TAAR1 (hTAAR1) ligands, we synthesized a new series of 1-amidino-4-phenylpiperazine derivatives (1–16) based on the application of a combined pharmacophore model/scaffold simplification strategy for an in-house series of biguanide-based TAAR1 agonists. Most of the novel compounds proved to be more effective than their prototypes, showing nanomolar EC50 values in functional activity at hTAAR1 and low general cytotoxicity (CC50 > 80 µM) when tested on the Vero-76 cell line. In this new series, the main determinant for TAAR1 agonism ability appears to result from the appropriate combination between the steric size and position of the substituents on the phenyl ring rather than from their different electronic nature, since both electron-withdrawing and electron donor groups are permitted. In particular, the ortho-substitution seems to impose a more appropriate spatial geometry to the molecule that entails an enhanced TAAR1 potency profile, as experienced, in the following order, by compounds 15 (2,3-diCl, EC50 = 20 nM), 2 (2-CH3, EC50 = 30 nM), 6 (2-OCH3, EC50 = 93 nM) and 3 (2-Cl, EC50 = 160 nM). Apart from the interest in them as valuable leads for the development of promising hTAAR1 agonists, these simple small molecules have further allowed us to identify the minimal structural requirements for producing an efficient hTAAR1 targeting ability.
36
McBride, Molly J., Sarah R. Pope, Kai Hu, C. Denise Okafor, Emily P. Balskus, J. Martin Bollinger, and Amie K. Boal. "Structure and assembly of the diiron cofactor in the heme-oxygenase–like domain of the N-nitrosourea–producing enzyme SznF." Proceedings of the National Academy of Sciences 118, no. 4 (January 19, 2021): e2015931118. http://dx.doi.org/10.1073/pnas.2015931118.
Анотація:
In biosynthesis of the pancreatic cancer drug streptozotocin, the tridomain nonheme-iron oxygenase SznF hydroxylates Nδ and Nω′ of Nω-methyl-l-arginine before oxidatively rearranging the triply modified guanidine to the N-methyl-N-nitrosourea pharmacophore. A previously published structure visualized the monoiron cofactor in the enzyme’s C-terminal cupin domain, which promotes the final rearrangement, but exhibited disorder and minimal metal occupancy in the site of the proposed diiron cofactor in the N-hydroxylating heme-oxygenase–like (HO-like) central domain. We leveraged our recent observation that the N-oxygenating µ-peroxodiiron(III/III) intermediate can form in the HO-like domain after the apo protein self-assembles its diiron(II/II) cofactor to solve structures of SznF with both of its iron cofactors bound. These structures of a biochemically validated member of the emerging heme-oxygenase–like diiron oxidase and oxygenase (HDO) superfamily with intact diiron cofactor reveal both the large-scale conformational change required to assemble the O2-reactive Fe2(II/II) complex and the structural basis for cofactor instability—a trait shared by the other validated HDOs. During cofactor (dis)assembly, a ligand-harboring core helix dynamically (un)folds. The diiron cofactor also coordinates an unanticipated Glu ligand contributed by an auxiliary helix implicated in substrate binding by docking and molecular dynamics simulations. The additional carboxylate ligand is conserved in another N-oxygenating HDO but not in two HDOs that cleave carbon–hydrogen and carbon–carbon bonds to install olefins. Among ∼9,600 sequences identified bioinformatically as members of the emerging HDO superfamily, ∼25% conserve this additional carboxylate residue and are thus tentatively assigned as N-oxygenases.
37
Zhou, Heyang, Niao Yang, Wei Li, Xuemi Peng, Jiaxiao Dong, Yuanying Jiang, Lan Yan, Dazhi Zhang, and Yongsheng Jin. "Exploration of Baicalein-Core Derivatives as Potent Antifungal Agents: SAR and Mechanism Insights." Molecules 28, no. 17 (August 30, 2023): 6340. http://dx.doi.org/10.3390/molecules28176340.
Анотація:
Baicalein (BE), the major component of Scutellaria Baicalensis, exhibited potently antifungal activity against drug-resistant Candida albicans, and strong inhibition on biofilm formation. Therefore, a series of baicalein-core derivatives were designed and synthesized to find more potent compounds and investigate structure–activity relationship (SAR) and mode of action (MoA). Results demonstrate that A4 and B5 exert a more potent antifungal effect (MIC80 = 0.125 μg/mL) than BE (MIC80 = 4 μg/mL) when used in combination with fluconazole (FLC), while the MIC80 of FLC dropped from 128 μg/mL to 1 μg/mL. SAR analysis indicates that the presence of 5-OH is crucial for synergistic antifungal activities, while o-dihydroxyls and vic-trihydroxyls are an essential pharmacophore, whether they are located on the A ring or the B ring of flavonoids. The MoA demonstrated that these compounds exhibited potent antifungal effects by inhibiting hypha formation of C. albicans. However, sterol composition assay and enzymatic assay conducted in vitro indicated minimal impact of these compounds on sterol biosynthesis and Eno1. These findings were further confirmed by the results of the in-silico assay, which assessed the stability of the complexes. Moreover, the inhibition of hypha of this kind of compound could be attributed to their effect on the catalytic subunit of 1,3-β-d-glucan synthase, 1,3-β-d-glucan-UDP glucosyltransferase and glycosyl-phosphatidylinositol protein, rather than inhibiting ergosterol biosynthesis and Eno1 activity by Induced-Fit Docking and Molecular Dynamics Simulations. This study presents potential antifungal agents with synergistic effects that can effectively inhibit hypha formation. It also provides new insights into the MoA.
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Hasan, Md Rifat, Ahad Amer Alsaiari, Burhan Zain Fakhurji, Mohammad Habibur Rahman Molla, Amer H. Asseri, Md Afsar Ahmed Sumon, Moon Nyeo Park, Foysal Ahammad, and Bonglee Kim. "Application of Mathematical Modeling and Computational Tools in the Modern Drug Design and Development Process." Molecules 27, no. 13 (June 29, 2022): 4169. http://dx.doi.org/10.3390/molecules27134169.
Анотація:
The conventional drug discovery approach is an expensive and time-consuming process, but its limitations have been overcome with the help of mathematical modeling and computational drug design approaches. Previously, finding a small molecular candidate as a drug against a disease was very costly and required a long time to screen a compound against a specific target. The development of novel targets and small molecular candidates against different diseases including emerging and reemerging diseases remains a major concern and necessitates the development of novel therapeutic targets as well as drug candidates as early as possible. In this regard, computational and mathematical modeling approaches for drug development are advantageous due to their fastest predictive ability and cost-effectiveness features. Computer-aided drug design (CADD) techniques utilize different computer programs as well as mathematics formulas to comprehend the interaction of a target and drugs. Traditional methods to determine small-molecule candidates as a drug have several limitations, but CADD utilizes novel methods that require little time and accurately predict a compound against a specific disease with minimal cost. Therefore, this review aims to provide a brief insight into the mathematical modeling and computational approaches for identifying a novel target and small molecular candidates for curing a specific disease. The comprehensive review mainly focuses on biological target prediction, structure-based and ligand-based drug design methods, molecular docking, virtual screening, pharmacophore modeling, quantitative structure–activity relationship (QSAR) models, molecular dynamics simulation, and MM-GBSA/MM-PBSA approaches along with valuable database resources and tools for identifying novel targets and therapeutics against a disease. This review will help researchers in a way that may open the road for the development of effective drugs and preventative measures against a disease in the future as early as possible.
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Raghuvanshi, Rinky, and Sandip B. Bharate. "Preclinical and Clinical Studies on Bryostatins, A Class of Marine-Derived Protein Kinase C Modulators: A Mini-Review." Current Topics in Medicinal Chemistry 20, no. 12 (June 1, 2020): 1124–35. http://dx.doi.org/10.2174/1568026620666200325110444.
Анотація:
: Bryostatins are complex macrolactones isolated from marine organisms Bryozoan Bugula neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well established, with the identification of key pharmacophoric features important for PKC modulation. The low natural abundance and the long synthetic route have prompted medicinal chemists to come-up with simplified analogs. Bryostatin skeleton comprises three pyran rings connected to each other to form a macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate the PKCα activity; however, the cyclic framework appears to be essential for the desired level of potency. Another simplified analog 17 ("picolog") exhibited potent and in-vivo efficacy against lymphoma. Bryostatin-1 (1) has shown an acceptable intravenous pharmacokinetic profile in mice and displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease. Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials; it has shown minimal effect as a single agent, however, provided encouraging results in combination with other chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with paclitaxel for esophageal cancer. Bryostatin-1 has also received orphan drug status for fragile X syndrome. Bryostatin-1 was also investigated in clinical studies for Alzheimer's disease and HIV infection. In a nutshell, the natural as well as synthetic bryostatins have generated a strong hope to emerge as treatment for cancer along with many other diseases.
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Hao, Wenhui, Shiying Che, Jinsheng Li, Jingyi Luo, Wanqiu Zhang, Yang Chen, Zijian Zhao, Hao Wei, and Weidong Xie. "Synthesis of Berberine and Canagliflozin Chimera and Investigation into New Antibacterial Activity and Mechanisms." Molecules 27, no. 9 (May 5, 2022): 2948. http://dx.doi.org/10.3390/molecules27092948.
Анотація:
Berberine is an isoquinoline alkaloid isolated from Chinese herbal medicines such as Coptis chinensis. It has many pharmacological actions, such as antibacterial, hypoglycemic, anti-inflammatory, and so on. However, due to the low lipophilicity of berberine, it is difficult to penetrate the bacterial cell membrane and also difficult to be absorbed orally and usually needs a relatively high dose to achieve the ideal effect. The purpose of this study is to transform the structure of berberine in order to improve the bioavailability of berberine and reduce the dosage. Moreover, we introduce a pharmacophore named Canagliflozin, a hypoglycemic drug (which was also found to have potential anti-bacterial activity) into BBR to see whether this new compound has more existed activities. We at first connected berberine with Canagliflozin, to form a new compound (BC) and see whether BC has synergic effects. We use microbroth dilution method to determine the minimum inhibitory concentration of BC, determine the bacterial growth with the enzyme labeling instrument, observe the formation of bacterial biofilm with crystal violet staining method, observe the bacterial morphology with field emission scanning electron microscope, and determine the intracellular protein with SDS-PAGE. The above indicators reflect the damage of BC to bacteria. New compound BC was successfully obtained by chemical synthesis. The minimal inhibitory concentration of compound BC on three bacteria was significantly better than that of berberine and canagliflozin alone and the combination of berberine and canagliflozin. Moreover, compound BC has obvious destructive effect on bacterial morphology and biofilm, and the compound also has destructive effect on intracellular proteins. Therefore, new compound BC has broad-spectrum antibacterial activity and the inhibitory effect of BC might play a role by destroying the integrity of biofilm and the intracellular protein of bacteria. In conclusion, we create a new molecular entity of berberine and Canagliflozin chimera and open up a new prospect for berberine derivatives in the treatment of bacterial infection.
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Ting, Jasmine U., Maria Carmen S. Tan, Vincent Antonio S. Ng, Stephani Joy Y. Macalino, Virgilio C. Linis та Glenn G. Oyong. "Molecular Simulations of Unexplored Philippine Plant Constituents on the Inhibition of the Proinflammatory Marker NF-κB p50 Subunit". Crystals 14, № 5 (4 травня 2024): 438. http://dx.doi.org/10.3390/cryst14050438.
Анотація:
Inflammation serves as a pivotal defense mechanism orchestrated by the innate immune system to safeguard cellular health against adversities. Nonetheless, dysregulated inflammatory responses can precipitate chronic inflammatory ailments, notably autoimmune disorders. Central to this process are various pathways, with studies highlighting the pivotal role of transcription factors within the nuclear factor-kappa B (NF-κB) signaling pathway in disease onset and progression. This study concentrates on the p50 homodimer protein, a key transcription factor pivotal for the expression of proinflammatory cytokine genes. To explore potential inhibitors of p50, we conducted in silico procedures to investigate fifty-eight unexplored compounds, derived from plants indigenous to the Philippines. Initial screenings for compound feasibility, through drug-likeness analyses, yielded positive outcomes for 34 compounds. Subsequent docking analyses revealed six compounds exhibiting binding energies (ranging from −3.7 to −4.2 kcal/mol) akin to or lower than the positive control, dexamethasone (−3.7 kcal/mol). These compounds include eudesm-11-en-4α-O-β-D-3-tigoyloxy-6-deoxy-glucopyranoside, wadeiol, grandiflorolide, eudesm-11-en-4α-O-β-D-3-senecioyloxy-6-deoxyglucopyranoside, α-pinene-7β-O-β-D-2- acetylglucopyranoside, and (2aβ,3α,5aβ,6β,7α,8aα)-6-[2-(3-furanyl)ethyl]-2a,3,4,5,5a,6,7,8,8a,8b- decahydro-2a,3-dihydroxy-6,7,8b-trimethyl-2H-naphtho[1-8-bc]furan-2-one. Interaction analyses revealed a common engagement of amino acid residues within the p50 DNA binding pocket, notably Arg57, Tyr60, Glu63, Lys244, Ala245, Pro246, Lys275, Arg308, Gln309, and Phe310, through hydrogen bonding, van der Waals forces, alkyl, and pi–alkyl interactions. Pharmacophore analysis underscored aromatic rings, hydroxyl, methyl, and methylene groups as pivotal for non-covalent interactions with p50. Additionally, root mean square fluctuation (RMSF) analysis demonstrated minimal residue fluctuations in p50 upon ligand binding compared to the ligand-free protein structure. In conclusion, the six shortlisted compounds exhibiting comparable binding affinities with dexamethasone hold promise as potential anti-inflammatory agents targeting the NF-κB p50 homodimer.
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Branco, Jessica R., Vanessa G. Oliveira, Amanda M. Esteves, Ingrid C. Chipoline, Miriam F. O. Lima, Fernanda C. S. Boechat, Fernando C. da Silva, et al. "A Novel Naphthotriazolyl-4-oxoquinoline Derivative that Selectively Controls Breast Cancer Cells Survival Through the Induction of Apoptosis." Current Topics in Medicinal Chemistry 18, no. 17 (November 26, 2018): 1465–74. http://dx.doi.org/10.2174/1568026618666180821142458.
Анотація:
Background: Breast cancer is a major cause of death among women worldwide. Treatment for breast cancer involves the surgical removal of cancer tissue, followed by chemotherapy. Although the treatment is efficient, especially when the cancer is detected early, recurrence is common and is often resistant to the previous treatment. Therefore, a constant search for efficient and novel drugs for the treatment of breast cancer is mandatory. Recently, triazole derivatives have shown promising effects against different types of cancer, revealing these molecules as putative anticancer drugs. Experimental: We have synthesized a series of naphthotriazolyl-4-oxoquinoline derivatives and tested their activity against a human breast cancer cell line. Among the compounds tested, we identified a molecule that killed the human breast cancer cell line MCF-7 with minimal effects on its noncancer counterpart, MCF10A. This effect was seen after 24 hours of treatment and persisted for additional 24 hours after treatment withdrawal. After 1 hour of treatment, the compound, here named 12c, promoted a decrease in cell glucose consumption and lactate production. Moreover, the cells treated with 12c for 1 hour showed diminished intracellular ATP levels with unaltered mitochondrial potential and increased reactive oxygen species production. Additionally, apoptosis was triggered after treatment with the drug for 1 hour. All of these effects are only observed with MCF-7 cells, and not MCF10A. These data show that 12c has selective activity against breast cancer cells and is a potential candidate for a novel anticancer drug. Results and Conclusion: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields, and one of them, 12c, exhibited strong and selective antitumor properties. The antitumor mechanism involves inhibition of glycolysis, diminished intracellular ATP levels, induction of ROS production and triggering of apoptosis. These effects are all selective for cancer cells, since noncancer cells are unaffected, and these effects can only be attributed to the whole molecule, as different pharmacophoric groups did not reproduce these effects.
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Lomovskaya, Olga, Kirk J. Nelson та Debora Rubio-Aparicio. "727. Potency of the β-Lactamase Inhibitor QPX7728 Is Minimally Affected by KPC Mutations that Reduce Potency of Ceftazidime–Avibactam". Open Forum Infectious Diseases 6, Supplement_2 (жовтень 2019): S326. http://dx.doi.org/10.1093/ofid/ofz360.795.
Анотація:
Abstract Background In the United States, carbapenem-resistant Enterobacteriaceae (CRE) are mainly represented by KPC-producing strains and ceftazidime–avibactam (C/A) is increasingly used to treat infections caused by KPC-producers. C/A resistant (C/A-R) mutants with mutations in blaKPC can be isolated in vitro and were reported in patients treated with C/A. QPX7728 (QPX) is a new ultra-broad-spectrum β-lactamase inhibitor based on a cyclic boronic acid pharmacophore with a potent activity against serine and metallo-β-lactamases. QPX in combination with meropenem (MER), M/Q, or cefepime (FEP), F/Q, has potent activity against all types of CRE (KPC, MBLs and OXA-48). The objective of these studies was to evaluate the activity of QPX in combination with various antibiotics against KPC-producing strains with C/A-R due to mutations in blaKPC. Methods Ten strains of KPC-producing Klebsiella pneumoniae with C/A MIC varied from 0.5 µg/mL to 8 µg/mL were used in resistance studies using C/A at 2x–8x the MIC (with avibactam [AVI] fixed at 4 µg/mL). Mutations in blaKPC were identified by sequence analysis. Ceftazidime (CAZ), MER and FEP MIC alone and with AVI and QPX (both BLIs at 4 µg/mL) were determined using the reference broth microdilution method. Five C/A-R clinical isolates with mutations in blaKPC were also included in the panel. Results Mutations in blaKPC that result in C/A resistance were selected in all strains. Mutants had 4- to 64-fold (16-fold average) increase in C/A MIC that varied from 16 to 128 μg/mL. In contrast, there was a 2-fold increase for CAZ-QPX MICs (MICs between ≤0.125 to 2 μg/mL. Similarly, there was no more than 2-fold increase in MER/QPX and FEP/QPX MICs, and the majority of mutants did not have an increase in MER/QPX or FEP/QPX MICs (MICs varied from ≤0.125 to 1 µg/mL). For five clinical C/A-R isolates, C/A, M/Q and F/Q MIC varied from 16 to ≥128 μg/mL, ≤0.125 to 4 μg/mL, and ≤0.125 to 2 μg/mL, respectively. Conclusion These data indicate that KPC mutations that affect the potency of C/A have minimal effect on the potency of QPX7728 combinations with either CAZ, MER or FEP indicating the potential differences in binding sites for these inhibitors in KPC. Further studies of QPX combinations are in progress. Disclosures All authors: No reported disclosures.
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Sokolova, K. V., V. V. Stavytskyi, S. О. Konovalova, O. A. Podpletnya, S. I. Kovalenko, and A. P. Avdeenko. "Design and search for prospective diuretics (CA II Inhibitors) among aroylhydrazones of esters quinone oxime using in silico and in vivo methodology." Medicni perspektivi 27, no. 4 (December 29, 2022): 27–37. http://dx.doi.org/10.26641/2307-0404.2022.4.271120.
Анотація:
The design and search for new selective inhibitors of CA II with a better pharmacological profile, which would cause minimal electrolyte disturbances in the body, remains an urgent problem of medical chemistry and pharmacology today. It is important that the discovered new classes of inhibitors do not always contain the main “pharmacophoric” function (sulfamide), which is characteristic of “classic” drugs (Acetazolamide, Methazolamide, Ethoxzolamide, Dorzolamide and others), but are derivatives of phenols, polyamines, coumarins/thiocoumarins, ureas, thioureas, hydroxamates, etc. These molecules also bind in the active site of the enzyme, but do not interact directly with the catalytic zinc ion or interact through zinc-coordinated water molecules/hydroxide ion. However, this leads to an increase in their selectivity and, as a result, pharmacological action. Continuing the search for compounds that affect urination, we were interested in aroylhydrazones of esters of quinone oxime. Firstly, they are characterized by certain structural features (dynamic and geometric isomerism); secondly, they exhibit redox properties; thirdly, the presence of aromatic fragments makes it possible to create a voluminous combinatorial library for analysis. These compounds are ligands in complexation reactions, and an additional increase in the number of hydrogen acceptors in the molecule due to structural modification will improve ligand-enzymatic interactions with carbonic anhydrase (CAII) and, as a result, reveal new promising diuretics. The aim – design and search for potential diuretics (CA II inhibitors) among aroylhydrazones of esters of quinone oxime using in silico, traditional synthesis and in vivo methodologies. Methods of organic synthesis, physico-chemical methods of analysis of organic compounds (NMR 1H-spectroscopy, elemental analysis). Prediction of affinity to the biological target, prediction of toxicity and lipophilicity of the combinatorial library of benzohydrazides O-aroyl esters of quinone oxime using computer services. The study of compounds affecting the excretory function of rat kidneys was carried out according to the generally accepted method of E.B.Berkhin with water load. The investigation of the probable mechanism was carried out using flexible molecular docking, as an approach to search for molecules that have affinity for human carbonic anhydrase type II (CA II). Macromolecular data of the crystal structure of CA II (PDB ID – 3HS4) were downloaded from the Protein Data Bank (PDB). The design was developed and the search for diuretic agents among benzohydrazides of O-aroyl esters of quinone oximes was developed using in silico methods (prediction of affinity, lipophilicity, toxicity and enzyme-ligand interactions), traditional organic synthesis, and in vivo methods (effect on excretory function of rat kidneys). The synthesis of benzohydrazides of O-aroyl esters of quinone oxime was carried out by the interaction of aroylhydrazines with 4-[(aroylimino)]cyclohexa-2,5-dien-1-ones. The structure of the synthesized compounds was confirmed by elemental analysis and 1H NMR spectra. Studies of the effect of synthesized compounds on the excretory function of rat kidneys allowed us to identify a number of promising compounds among aroylhydrazones of quinonexime esters, which increase daily diuresis by 54.2-352.8% compared to the control group. At the same time, it was established that the most active was N'-(4-[(2-chlorobenzoyloxy)imino]cyclohexa-2,5-dien-1-ylidene)-3-nitrobenzohydrazide, which increased daily diuresis by 352.8% in comparison with the control group, while exceeding the effect of “Hydrochlorothiazide” (170.8%). The developed and implemented strategy for the search for diuretics among benzohydrazides of O-aroylesters of quinone oxime allowed the identification of an effective compound, which in terms of diuretic effect exceeds the comparison drug “Hydrochlorothiazide”. Visualization of the molecular docking of the active compounds showed that their geometry makes it difficult to place them in the pocket of the active site of CA II, but the pronounced diuretic effect can also be associated with their ability to form coordination bonds with the zinc cation. The obtained results justify the further targeted search for potential diuretics among this class of compounds for a more detailed understanding and study of the mechanism of action.
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Sacco, Antonio, Cinzia Federico, Arianna Giacomini, Cinzia Caprio, Federica Maccarinelli, Katia Todoerti, Vanessa Favasuli, et al. "FGF/FGFR Axis-Blockade Leads to Anti-Tumor Activity in Waldenstrom's Macroglobulinemia By Silencing MYD88." Blood 136, Supplement 1 (November 5, 2020): 43–44. http://dx.doi.org/10.1182/blood-2020-136523.
Анотація:
The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenstrom's Macroglobulinemia (WM). Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We investigated the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule, NSC12, a small molecule identified using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2. By interrogating the transcriptome signature of patients' BM-derived CD19-positive cells (GEO9656, GEO6691), we found a significant enrichment of FGF/FGFR-driven signaling cascades, including PI3K-AKT, MAPK and STAT3 pathways (FDR<0.25; P<0.05); coupled with higher expression of FGFs (FGF2, FGF7, FGF12, FGF18; P<0.05) in WM cells as compared to their normal cellular counterpart. FGFRs are also shown to be overexpressed in WM. We performed transcriptome profiling of NSC12-treated WM cells, confirming the blockade of the FGFR-signaling blockade; and, importantly, we discovered the efficacious silencing of MYD88 and MYD88-dopwnstream target HCK in WM cells. These findings were confirmed at protein level, showing inhibition of MYD88-driven pathways, such as BTK-, and SYK-phosphorylation. As a further demonstration of the functional impact of NSC12-dependent targeting of MYD88, we could confirm the inhibition of both canonical and non-canonical NF-kB in NSC12-treated WM cells, as assessed at nuclear protein level by WB and by using the NFkB activity assay. In addition, the NSC12-dependent inhibition of MYD88 resulted in silencing of the MAPK-ERK signaling cascade, thus leading to NSC12-induced Myc-silencing in WM cells. We next confirmed the efficacy of NSC12 in silencing bone marrow stromal cell (BMSC)-induced FGFR3 phosphorylation; paralleled by inhibition of of pro-survival pathways, including pAKT, the AKT-downstream pGSK3β; p-ERK; and p-STAT3. Functional sequelae of the FGF/FGFR blockade in WM cells were studied, demonstrating inhibition of WM cell growth, induction of apoptosis, enhanced ER stress and initiation of UPR. Of note, anti-WM activity of NSC12 was also documented using primary bone marrow-derived CD19+ cells isolated from patients with WM. In contrast, NSC12 did not show cytotoxicity on PBMC-derived CD19+ cells isolated from healthy donors. The anti-WM activity exerted by NSC12 was confirmed also within the context of the supportive bone marrow milieu, as shown both in vitro and in vivo. BCWM.1, MWCL1 cells were cultured with NSC12 in the presence or absence of primary WM BMSCs: adherence of WM cells to BMSCs triggered a significant increase in the proliferation, which was inhibited by NSC12in a dose-dependent manner (P<0.05). Using a disseminated humanized WM model, BCWM.1 M-Cherry-Luc tumor-bearing mice were treated with either NSC12 or vehicle control. NSC12-treated mice presented with a significant inhibition of WM tumor growth as demonstrated by bioluminescence imaging analysis. NSC12-dependent reduction of WM tumor cell BM infiltration was confirmed by IHC performed on harvested femurs, in comparison to vehicle-treated mice. Importantly, we assessed MYD88-mRNA expression using harvested bone marrow femurs; and found a significant reduction of MYD88- and MYD88-downstream target HCK in NSC12-treated mice was confirmed ex vivo (P<0.05). Overall, our studies are reporting on the use of NSC12, as a novel potential therapeutic strategy to specifically halt the FGF/FGFR axis in WM; and demonstrate how the observed anti-WM activity exerted by NSC12 may be driven, at least in part, by inhibition of MYD88. Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Rossi:Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Roccaro:Amgen: Other; AstraZeneca: Research Funding; Celgene: Other; Janssen: Other; Italian Association for Cancer Research (AIRC): Research Funding; Transcan2-ERANET: Research Funding; European Hematology Association: Research Funding.
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Luthra, Pratibha Mehta, and Nitin Kumar. "Progress and development of C-3, C-6, and N-9 position substituted carbazole integrated molecular hybrid molecules as potential anticancer agents." Mini-Reviews in Medicinal Chemistry 21 (May 21, 2021). http://dx.doi.org/10.2174/1389557521666210521221808.
Анотація:
Abstract: The carbazole skeleton, a key structural motif occurring naturally or chemically synthesized, have shown various biological activities. Molecular hybridization based on the combination of two or more bioactive pharmacophores has been an important tool to convert the potent structural leads to form new hybrid compounds with improved biological activity. In recent years, modifications/substitutions of the carbazole motif at C3, C6, N9 position have been carried to develop novel carbazole based potential anticancer agents in the cancer therapy. In the last fifteen years, several compounds based on carbazole core integrated to pharmacologically active molecular hybrid having active pharmacophore such as 1,3,4-thiadiazole, thiazole, guanidine, sulfonamides, glyoxamides, imidazole, phenanthrene, rhodamine, chalcones, imidazopyridine, platinum 2H-chromen-2-one, hydrazones, piperazine, Isoxazole-thiadiazole, pyrazole etc. have been synthesized showing anticancer profile at sub-micromolar to nano-molar concentrations. We have thoroughly reviewed the design, progress and development of C-3, C-6, and N-9 position substituted carbazole derivatives integrated with various medicinally active pharmacophore as potential anticancer agents evaluated against various cancer cell lines. Additionally, the anticancer mechanism and in vivo activity of the reported compounds have been discussed. This study will support in designing of a new pharmacophore that can be linked to carbazole motif for development for new, potent and target specific anticancer drugs with improved pharmacokinetics and minimal side effects.
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Whitehouse, Rebecca L., Wesam S. Alwan, Olga V. Ilyichova, Ashley J. Taylor, Indu R. Chandrashekaran, Biswaranjan Mohanty, Bradley C. Doak, and Martin J. Scanlon. "Fragment screening libraries for the identification of protein hot spots and their minimal binding pharmacophores." RSC Medicinal Chemistry, 2022. http://dx.doi.org/10.1039/d2md00253a.
Анотація:
Small molecule interaction hotpots were identified by screening small, low complexity fragments using X-ray crystallography. These hot spots include cryptic pockets and provide pharmacophore mapping that may be used in structure-based drug design.
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Singh, Shailja, and Shrawan Kumar Mangawa. "Ferrocene Derivatives as New Generation of Antimalarial Agents: Opportunity or Illusion?" Current Topics in Medicinal Chemistry 23 (February 28, 2023). http://dx.doi.org/10.2174/1568026623666230228153114.
Анотація:
Abstract: Despite significant scientific progress over the last two decades, malaria remains a global burden that causes thousands of deaths every year. In the absence of effective and practical preventive measures, the only current option for reducing the mortality and morbidity of malaria is chemotherapy. However, due to the minimal stock of active antiparasitic analogs, issues of toxicity, and the repeated appearance of drug resistance, scientists must broaden the arsenal of existing therapies beyond conventional medicinal chemistry. To curb this menace, a series of potential metal-based hybrids have been synthesized and screened. Ferrocene is one of the potent organometallic candidates and the hybridization of ferrocene with other pharmacophores results in compounds with enhanced biological activities. Many researchers have reported the ferrocene compounds as potent pharmacophores and useful as anticancer and antimalarial agents when hybridized with other pharmaceutical hybrids. Drug, such as Ferroquine (FQ, SSR97193), is currently the most advanced organometallic compound developed from the hybridization of ferrocene and chloroquine and has demonstrated great potency in clinical trials against both drug-sensitive and drug-resistant malaria. Not only ferroquine but its derivatives have shown significant activity as antimalarial agents. The present review focuses on the discovery of FQ, the hypothesis of its mode of action, and recent clinical trials of ferrocene compounds as a new class of antimalarial agents. The structure-activity relationship (SAR) of ferrocene derivatives is also discussed to provide insight into the rational design of more effective antimalarial candidates. Finally, efforts have been made to discuss the future expectations for ferrocene-based antimalarial drugs.
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Kayastha, Forum, Noah B. Herrington, Bandish Kapadia, Anirban Roychowdhury, Nahid Nanaji, Glen E. Kellogg, and Ronald B. Gartenhaus. "Novel eIF4A1 inhibitors with anti‐tumor activity in lymphoma." Molecular Medicine 28, no. 1 (September 4, 2022). http://dx.doi.org/10.1186/s10020-022-00534-0.
Анотація:
Abstract Background Deregulated translation initiation is implicated extensively in cancer initiation and progression. It is actively pursued as a viable target that circumvents the dependency on oncogenic signaling, a significant factor in current strategies. Eukaryotic translation initiation factor (eIF) 4A plays an essential role in translation initiation by unwinding the secondary structure of messenger RNA (mRNA) upstream of the start codon, enabling active ribosomal recruitment on the downstream genes. Several natural product molecules with similar scaffolds, such as Rocaglamide A (RocA), targeting eIF4A have been reported in the last decade. However, their clinical utilization is still elusive due to several pharmacological limitations. In this study we identified new eIF4A1 inhibitors and their possible mechanisms. Methods In this report, we conducted a pharmacophore-based virtual screen of RocA complexed with eIF4A and a polypurine RNA strand for novel eIF4A inhibitors from commercially available compounds in the MolPort Database. We performed target-based screening and optimization of active pharmacophores. We assessed the effects of novel compounds on biochemical and cell-based assays for efficacy and mechanistic evaluation. Results We validated three new potent eIF4A inhibitors, RBF197, RBF 203, and RBF 208, which decreased diffuse large B-cell lymphoma (DLBCL) cell viability. Biochemical and cellular studies, molecular docking, and functional assays revealed that thosenovel compounds clamp eIF4A into mRNA in an ATP-independent manner. Moreover, we found that RBF197 and RBF208 significantly depressed eIF4A-dependent oncogene expression as well as the colony formation capacity of DLBCL. Interestingly, exposure of these compounds to non-malignant cells had only minimal impact on their growth and viability. Conclusions Identified compounds suggest a new strategy for designing novel eIF4A inhibitors.
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Rath, Santosh Kumar, Sudip Kumar Mandal, Agnidipta Das, Anindya Bose, Vagish Dwibedi, Paramita Ganguly, Sipra Sarkar, Ranjana Prakash, Biplab Kumar Dey, and Sanjeet Mandal. "Hetero Cyclic Compounds in the Treatment of Triple-Negative Breast Cancer." Current Cancer Therapy Reviews 19 (December 30, 2022). http://dx.doi.org/10.2174/1573394719666221230111838.
Анотація:
Abstract: Triple-negative breast cancer (TNBC) holds just about 15% of all breast tumours and subtypes of breast cancer with distinct characteristics of negative expressions for the progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2. Unfortunately, treatment options for TNBCs are minimal. Most currently available therapies proved inefficient in holding back this aggressive natural treatment of TNBC, in most cases calling for an immediate need for more effective and safer anti-TNBC agents. Based on research reported in recent years, this review presents the report's overview of anti-TNBC compounds and their efficacy, being classified according to the structures. Breast Cancer type 1 and type 2 genes (BRCA1/2) mutations are associated with TNBC. Poly (ADP-Ribose) Polymerases (PARPs) are a family of enzymes involved in numerous cellular processes, including DNA repair. PARP-1 inhibition is involved in the loss of DNA repair via BRCA-dependent mechanisms. PARP-1 inhibitors like Olaparib, Rucaparib, Niraparib, and Talazoparib have proved as promising therapeutic medications as monotherapy and in combination with cytotoxic therapy or radiotherapy in various types of cancers. This review is focused on presenting the status of therapeutics against TNBC. The critical spotlight of this review is to encapsulate the versatility and notable success of heterocyclic pharmacophores-based molecules in treating TNBC.