Journal articles: 'Docking of ATP analogs'

1

Choi, Kyudam, Yurim Lee, and Cheongwon Kim. "An In Silico Study for Expanding the Utility of Cannabidiol in Alzheimer’s Disease Therapeutic Development." International Journal of Molecular Sciences 24, no. 21 (November 6, 2023): 16013. http://dx.doi.org/10.3390/ijms242116013.

Full text

Abstract:

Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer’s disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic algorithm combined with a molecular docking system. As a result, we identified six targets associated with AD: Endothelial NOS (ENOS), Myeloperoxidase (MPO), Apolipoprotein E (APOE), Amyloid-beta precursor protein (APP), Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and Presenilin-1 (PSEN1). Furthermore, we generated CBD analogs for each target that optimize for all desired drug-likeness properties and physicochemical property filters, resulting in improved pIC50 values and docking scores compared to CBD. Molecular dynamics (MD) simulations were applied to analyze each target’s CBD and highest-scoring CBD analogs. The MD simulations revealed that the complexes of ENOS, MPO, and ADAM10 with CBD exhibited high conformational stability, and the APP and PSEN1 complexes with CBD analogs demonstrated even higher conformational stability and lower interaction energy compared to APP and PSEN1 complexes with CBD. These findings demonstrated the capable binding of the six identified targets with CBD and the enhanced binding stability achieved with the developed CBD analogs for each target.

APA, Harvard, Vancouver, ISO, and other styles

2

Elsawi, Ahmed E., Mai I. Shahin, Hager A. Elbendary, Tarfah Al-Warhi, Fatma E. Hassan, and Wagdy M. Eldehna. "1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking." Pharmaceuticals 17, no. 1 (January 8, 2024): 81. http://dx.doi.org/10.3390/ph17010081.

Full text

Abstract:

Targeting the VEGFR-2 signaling pathway is an inveterate approach toward combating pancreatic and hepatocellular cancers. Based on Sunitinib, the FDA-approved VEGFR-2 inhibitor, novel indolin-2-one-triazole hybrids were designed and synthesized as anti-hepatocellular and anti-pancreatic cancer agents with VEGFR-2 inhibitory activity. All the targeted compounds were assessed for their anti-cancer activity, revealing IC50 values extending from 0.17 to 4.29 µM for PANC1 and 0.58 to 4.49 µM for HepG2 cell lines. An extensive SAR study was conducted to explore the effect of different substituents along with N-alkylation. The potent anti-cancer analogs 11d, 11e, 11g, 11k and 14c were evaluated for their VEGFR-2 inhibitory actions, where their IC50 values ranged from 16.3 to 119.6 nM compared to Sorafenib, which revealed an IC50 of 29.7 nM, having compound 11d as the most active analog. An in silico ADME study was performed to confirm the drug-likeness of the synthesized compounds. Finally, molecular docking simulation was conducted for the most potent VEGFR-2 inhibitor (11d), demonstrating the strong binding with the vital amino acid residues of the VEGFR-2 ATP binding site.

APA, Harvard, Vancouver, ISO, and other styles

3

Wu, Yifei, Tze-chen Hsieh, Joseph M. Wu, Xiaoxiao Wang, Joshua S. Christopher, Amanda H. Pham, Justin David-Li Swaby, Lei Lou, and Zhong-Ru Xie. "Elucidating the Inhibitory Effect of Resveratrol and Its Structural Analogs on Selected Nucleotide-Related Enzymes." Biomolecules 10, no. 9 (August 22, 2020): 1223. http://dx.doi.org/10.3390/biom10091223.

Full text

Abstract:

Resveratrol, the most widely studied natural phytochemical, has been shown to interact with different target proteins. Previous studies show that resveratrol binds and inhibits DNA polymerases and some other enzymes; however, the binding and functioning mechanisms remain unknown. The elucidated knowledge of inhibitory mechanisms of resveratrol will assist us in new drug discovery. We utilized molecular docking and molecular dynamics (MD) simulation to reveal how resveratrol and structurally similar compounds bind to various nucleotide-dependent enzymes, specifically, DNA polymerases, HIV-1 reverse transcriptase, and ribonucleotide reductase. The results show that resveratrol and its analogs exert their inhibitory effects by competing with the substrate dNTPs in these enzymes and blocking elongation of chain polymerization. In addition, the results imply that resveratrol binds to a variety of other ATP-/NTP-binding proteins.

APA, Harvard, Vancouver, ISO, and other styles

4

Jayaraj, Premkumar, Chandrakala A. Narasimhulu, Andrei Maiseyeu, Rekha Durairaj, Shashidhar Rao, Sanjay Rajagopalan, Sampath Parthasarathy, and Rajagopal Desikan. "Methoxyphenol derivatives as reversible inhibitors of myeloperoxidase as potential antiatherosclerotic agents." Future Medicinal Chemistry 12, no. 2 (January 2020): 95–110. http://dx.doi.org/10.4155/fmc-2019-0080.

Full text

Abstract:

Aim: To evaluate new chemical entities, based on ferulic acid scaffolds, as reversible myeloperoxidase inhibitors (MPOI). Methodology & results: In silico docking studies are performed with MPO protein as a target for several ferulic acid analogs followed by multiple in vitro assays to validate this approach. Two lead compounds 2a and 3 are identified with optimum docking and IC50 values: -7.95 kcal/mol, 0.9 μM and -8.35 kcal/mol, 8.5 μM, respectively. These MPOIs are able to inhibit oxidation of high-density lipoprotein and further promoted functionality of high-density lipoprotein. Conclusion: Lead analogs are potent MPOIs that exert specific effects on MPO-mediated oxidation as well as inflammatory pathways. It also acts as promoters of cholesterol efflux that sheds light on pharmacological approach in atherosclerosis treatment.

APA, Harvard, Vancouver, ISO, and other styles

5

Lande, Duc Hoàng, Abed Nasereddin, Arne Alder, Tim W. Gilberger, Ron Dzikowski, Johann Grünefeld, and Conrad Kunick. "Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones." Molecules 26, no. 16 (August 5, 2021): 4739. http://dx.doi.org/10.3390/molecules26164739.

Full text

Abstract:

Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

APA, Harvard, Vancouver, ISO, and other styles

6

Pislyagin, Evgeny A., Ekaterina S. Menchinskaya, Irina N. Gladkikh, Aleksandra N. Kvetkina, Oksana V. Sintsova, Darya V. Popkova, Sergei A. Kozlovskiy, et al. "Recombinant Analogs of Sea Anemone Kunitz-Type Peptides Influence P2X7 Receptor Activity in Neuro-2a Cells." Marine Drugs 21, no. 3 (March 20, 2023): 192. http://dx.doi.org/10.3390/md21030192.

Full text

Abstract:

Purinergic P2X7 receptors (P2X7) have now been proven to play an important role and represent an important therapeutic target in many pathological conditions including neurodegeneration. Here, we investigated the impact of peptides on purinergic signaling in Neuro-2a cells through the P2X7 subtype in in vitro models. We have found that a number of recombinant peptides, analogs of sea anemone Kunitz-type peptides, are able to influence the action of high concentrations of ATP and thereby reduce the toxic effects of ATP. The influx of calcium, as well as the fluorescent dye YO-PRO-1, was significantly suppressed by the studied peptides. Immunofluorescence experiments confirmed that the peptides reduce the P2X7 expression level in neuronal Neuro-2a cells. Two selected active peptides, HCRG1 and HCGS1.10, were found to specifically interact with the extracellular domain of P2X7 and formed stable complexes with the receptor in surface plasmon resonance experiments. The molecular docking approach allowed us to establish the putative binding sites of the most active HCRG1 peptide on the extracellular domain of the P2X7 homotrimer and propose a mechanism for regulating its function. Thus, our work demonstrates the ability of the Kunitz-type peptides to prevent neuronal death by affecting signaling through the P2X7 receptor.

APA, Harvard, Vancouver, ISO, and other styles

7

Zhang, Xiaozhe, Shaodong Shi, Yang Su, Xiaoli Yang, Sining He, Xiuyan Yang, Jing Wu, Jian Zhang, and Feng Rao. "Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate–mediated regulation of cullin–RING ligase and sensitize cancer cells to MLN4924/pevonedistat." Journal of Biological Chemistry 295, no. 30 (June 3, 2020): 10281–92. http://dx.doi.org/10.1074/jbc.ra120.014375.

Full text

Abstract:

Inositol hexakisphosphate (IP6) is an abundant metabolite synthesized from inositol 1,3,4,5,6-pentakisphosphate (IP5) by the single IP5 2-kinase (IP5K). Genetic and biochemical studies have shown that IP6 usually functions as a structural cofactor in protein(s) mediating mRNA export, DNA repair, necroptosis, 3D genome organization, HIV infection, and cullin–RING ligase (CRL) deneddylation. However, it remains unknown whether pharmacological perturbation of cellular IP6 levels affects any of these processes. Here, we performed screening for small molecules that regulate human IP5K activity, revealing that the antiparasitic drug and polysulfonic compound suramin efficiently inhibits IP5K in vitro and in vivo. The results from docking experiments and biochemical validations suggested that the suramin targets IP5K in a distinct bidentate manner by concurrently binding to the ATP- and IP5-binding pockets, thereby inhibiting both IP5 phosphorylation and ATP hydrolysis. NF449, a suramin analog with additional sulfonate moieties, more potently inhibited IP5K. Both suramin and NF449 disrupted IP6-dependent sequestration of CRL by the deneddylase COP9 signalosome, thereby affecting CRL activity cycle and component dynamics in an IP5K-dependent manner. Finally, nontoxic doses of suramin, NF449, or NF110 exacerbate the loss of cell viability elicited by the neddylation inhibitor and clinical trial drug MLN4924/pevonedistat, suggesting synergistic ef-fects. Suramin and its analogs provide structural templates for designing potent and specific IP5K inhibitors, which could be used in combination therapy along with MLN4924/pevonedistat. IP5K is a potential mechanistic target of suramin, accounting for suramin's therapeutic effects.

APA, Harvard, Vancouver, ISO, and other styles

8

Reddy, K. Kumar, R. S. Rathore, P. Srujana, R. R. Burri, C. Ravikumar Reddy, M. Sumakanth, Pallu Reddanna, and M. Rami Reddy. "Performance Evaluation of Docking Programs- Glide, GOLD, AutoDock & SurflexDock, Using Free Energy Perturbation Reference Data: A Case Study of Fructose-1, 6-bisphosphatase-AMP Analogs." Mini-Reviews in Medicinal Chemistry 20, no. 12 (July 23, 2020): 1179–87. http://dx.doi.org/10.2174/1389557520666200526183353.

Full text

Abstract:

Background: The accurate ranking of analogs of lead molecules with respect to their estimated binding free energies to drug targets remains highly challenging in molecular docking due to small relative differences in their free energy values. Methods: Free energy perturbation (FEP) method, which provides the most accurate relative binding free energy values were earlier used to calculate free energies of many ligands for several important drug targets including Fructose-1,6-BisphosPhatase (FBPase). The availability of abundant structural and experimental binding affinity data for FBPase inhibitors provided an ideal system to evaluate four widely used docking programs, AutoDock, Glide, GOLD and SurflexDock, distinct from earlier comparative evaluation studies. Results: The analyses suggested that, considering various parameters such as docking pose, scoring and ranking accuracy, sensitivity analysis and newly introduced relative ranking score, Glide provided reasonably consistent results in all respects for the system studied in the present work. Whereas GOLD and AutoDock also demonstrated better performance, AutoDock results were found to be significantly superior in terms of scoring accuracy compared to the rest. Conclusion: Present analysis serves as a useful guide for researchers working in the field of lead optimization and for developers in upgradation of the docking programs.

APA, Harvard, Vancouver, ISO, and other styles

9

Tanneeru, Karunakar, Bandi Madhusudhan Reddy, and Lalitha Guruprasad. "Three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis and molecular docking of ATP-competitive triazine analogs of human mTOR inhibitors." Medicinal Chemistry Research 21, no. 7 (April 6, 2011): 1207–17. http://dx.doi.org/10.1007/s00044-011-9629-x.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Amin, Md Ruhul, Farhana Yasmin, Mohammed Anowar Hosen, Sujan Dey, Shafi Mahmud, Md Abu Saleh, Talha Bin Emran, et al. "Synthesis, Antimicrobial, Anticancer, PASS, Molecular Docking, Molecular Dynamic Simulations & Pharmacokinetic Predictions of Some Methyl β-D-Galactopyranoside Analogs." Molecules 26, no. 22 (November 20, 2021): 7016. http://dx.doi.org/10.3390/molecules26227016.

Full text

Abstract:

A series of methyl β-D-galactopyranoside (MGP, 1) analogs were selectively acylated with cinnamoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to yield 6-O-substitution products, which was subsequently converted into 2,3,4-tri-O-acyl analogs with different acyl halides. Analysis of the physicochemical, elemental, and spectroscopic data of these analogs revealed their chemical structures. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) showed promising antifungal functionality comparing to their antibacterial activities. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests were conducted for four compounds (4, 5, 6, and 9) based on their activity. MTT assay showed low antiproliferative activity of compound 9 against Ehrlich’s ascites carcinoma (EAC) cells with an IC50 value of 2961.06 µg/mL. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties whereas molecular docking identified potential inhibitors of the SARS-CoV-2 main protease (6Y84). A 150-ns molecular dynamics simulation study revealed the stable conformation and binding patterns in a stimulating environment. In-silico ADMET study suggested all the designed molecules to be non-carcinogenic, with low aquatic and non-aquatic toxicity. In summary, all these antimicrobial, anticancer and in silico studies revealed that newly synthesized MGP analogs possess promising antiviral activity, to serve as a therapeutic target for COVID-19.

APA, Harvard, Vancouver, ISO, and other styles

11

de Souza, Amanda Bubula, Leonardo Pereira de Araújo, Amanda Almeida Morais, Leandro Marcos Santos, Yana Cristina Albanez Santos, Cássia Milene Ribeiro Lopes, Paulo Vinicius Sanches Daltro de Carvalho, Syed Shah Hassan, and Nelson José Freitas da Silveira. "In silico analysis for the proposal of new drugs against the phosphoprotein nucleocapsid of the severe acute respiratory syndrome coronavirus 2 virus." Innovative Medicines & Omics 1, no. 1 (August 22, 2024): 3731. http://dx.doi.org/10.36922/imo.3731.

Full text

Abstract:

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which began in late 2019, has resulted in approximately seven million deaths worldwide. This underscores the urgent need for vaccine and drug development. In silico techniques, especially molecular docking, provide promising means for discovering new treatments. This study aimed to identify novel compounds with potential activity against the nucleocapsid protein of SARS-CoV-2 using drug repositioning and bioisosterism techniques. We performed molecular docking with 20,115 compounds from the BindingDB database. The protein, obtained from the Protein Data Bank (PDB ID: 6WZQ), was prepared using MGLTools software, including protonation and removal of co-crystallized ligands and water molecules. We defined the binding site at the protein’s active site and used AutoDock Vina software for molecular docking, ranking the results based on relative binding energy. Interactions were visualized using Pymol and LigPlot+ software, focusing on hydrogen bonds and hydrophobic interactions. Compound BDBM6732 showed the most favorable binding energy (−13.4 kcal/mol), similar to the control compound suramin (−13.3 kcal/mol), but it was predicted to carry risks for hepatotoxicity and mutagenesis. We generated bioisosteres, resulting in two candidate analog compounds with superior affinity to four compounds referenced in the scientific literature, two of which had their activity validated in in vivo testing. These results suggest that the two analogs may potentially combat SARS-CoV-2 by binding to the nucleocapsid protein. However, validation in both in vitro and in vivo settings is essential.

APA, Harvard, Vancouver, ISO, and other styles

12

Abdelkrim, Yosser Zina, Emna Harigua-Souiai, Imen Bassoumi-Jamoussi, Mourad Barhoumi, Josette Banroques, Khadija Essafi-Benkhadir, Michael Nilges, Arnaud Blondel, N. Kyle Tanner, and Ikram Guizani. "Enzymatic and Molecular Characterization of Anti-Leishmania Molecules That Differently Target Leishmania and Mammalian eIF4A Proteins, LieIF4A and eIF4AMus." Molecules 27, no. 18 (September 10, 2022): 5890. http://dx.doi.org/10.3390/molecules27185890.

Full text

Abstract:

Previous investigations of the Leishmania infantum eIF4A-like protein (LieIF4A) as a potential drug target delivered cholestanol derivatives inhibitors. Here, we investigated the mode of action of cholesterol derivatives as a novel scaffold structure of LieIF4A inhibitors on the RNA-dependent ATPase activity of LieIF4A and its mammalian ortholog (eIF4AI). We compared their biochemical effects on RNA-dependent ATPase activities of both proteins and investigated if rocaglamide, a known inhibitor of eIF4A, could affect LieIF4A as well. Kinetic measurements were conducted at different concentrations of ATP, of the compound and in the presence of saturating whole yeast RNA concentrations. Kinetic analyses showed different ATP binding affinities for the two enzymes as well as different sensitivities to 7-α-aminocholesterol and rocaglamide. The 7-α-aminocholesterol inhibited LieIF4A with a higher binding affinity relative to cholestanol analogs. Cholesterol, another tested sterol, had no effect on the ATPase activity of LieIF4A or eIF4AI. The 7-α-aminocholesterol demonstrated an anti-Leishmania activity on L. infantum promastigotes. Additionally, docking simulations explained the importance of the double bond between C5 and C6 in 7-α-aminocholesterol and the amino group in the C7 position. In conclusion, Leishmania and mammalian eIF4A proteins appeared to interact differently with effectors, thus making LieIF4A a potential drug against leishmaniases.

APA, Harvard, Vancouver, ISO, and other styles

13

Lv, Han, Yongli Du, Xiehuang Sheng, Zhipei Gao, and Jingkang Shen. "Molecular modeling studies of [4-(3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine-based CDK4 inhibitors." Future Medicinal Chemistry 13, no. 16 (August 2021): 1317–39. http://dx.doi.org/10.4155/fmc-2020-0393.

Full text

Abstract:

Aim: CDK4 is a promising target for breast cancer therapy. This study aimed to explore the structure–activity relationship of CDK4 inhibitor abemaciclib analogs and design potent CDK4 inhibitors for breast cancer treatment. Methods & results: A faithful 3D quantitative structure–activity relationship model was established by molecular docking, comparative molecular field analysis and comparative molecular similarity index analysis based on 56 abemaciclib analogs. Molecular dynamics simulation studies revealed the key residues of the interaction between CDK4 and inhibitors. Four novel inhibitors with satisfactory predicted binding affinity to CDK4 were designed. Conclusion: The 3D quantitative structure–activity relationship and molecular dynamics simulation studies provide valuable insight into the development of novel CDK4 inhibitors.

APA, Harvard, Vancouver, ISO, and other styles

14

K Singla, Rajeev, Piya Paul, Pawan G Nayak, and Varadaraj Bhat G. "Investigation of Anthramycin Analogs Induced Cell Death in MCF-7 Breast Cancer Cells." Indo Global Journal of Pharmaceutical Sciences 02, no. 04 (2012): 383–89. http://dx.doi.org/10.35652/igjps.2012.44.

Full text

Abstract:

1,5-Benzodiazepines were synthesized using chalcone & o-phenylene diamine. Their structures were characterized using physical & spectral data. These molecules are analogous to anthracin, henceforth evaluated for their anti-breast cancer activity, using in vitro model MTT assay against MCF-7 cell line. Results revealed that these molecules are having potential growth inhibitory effect on the MCF-7 cell line, and certainly better than that of standard cisplatin. Docking studies revealed that these 1,5- benzodiazepine molecules may be working by inhibiting tyrosine kinase receptor, ErbB4 of human breast adenocarcinoma cell line(MCF-7/Michigan Cancer Foundation-7). © 2011 IGJPS. All rights reserved.

APA, Harvard, Vancouver, ISO, and other styles

15

Czeleń, Przemysław, and Beata Szefler. "The Oxindole Derivatives, New Promising GSK-3β Inhibitors as One of the Potential Treatments for Alzheimer’s Disease—A Molecular Dynamics Approach." Biology 10, no. 4 (April 15, 2021): 332. http://dx.doi.org/10.3390/biology10040332.

Full text

Abstract:

The glycogen synthase kinase 3β (GSK-3β) is a protein kinase involved in regulating numerous physiological processes such as embryonic development, transcription, insulin action, cell division cycle and multiple neuronal functions. The overexpression of this enzyme is related to many diseases such as schizophrenia, Alzheimer’s disease, diabetes and cancer. One of the basic methods of treatment in these cases is the usage of ATP-competitive inhibitors. A significant group of such compounds are indirubin and its analogs, e.g., oxindole derivatives. The compounds considered in this work are 112 newly designed oxindole derivatives. In the first stage, such molecular properties of considered compounds as toxicity and LogP were estimated. The preliminary analysis of the binding capabilities of considered compounds towards the GSK-3β active site was conducted with the use of the docking procedure. Based on obtained molecular properties and docking simulations, a selected group of complexes that were analyzed in the molecular dynamics stage was nominated. The proposed procedure allowed for the identification of compounds such as Oxind_4_9 and Oxind_13_10, which create stable complexes with GSK-3β enzyme and are characterized by the highest values of binding affinity. The key interactions responsible for stabilization of considered ligand–protein complexes were identified, and their dynamic stability was also determined. Comparative analysis including analyzed compounds and reference molecule 3a, which is also an oxindole derivative with a confirmed inhibitory potential towards GSK3B protein, clearly indicates that the proposed compounds exhibit an analogous binding mechanism, and the obtained binding enthalpy values indicate a slightly higher binding potential than the reference molecule.

APA, Harvard, Vancouver, ISO, and other styles

16

Babu Jatavath, Mohan, Sree Kanth Sivan, Yamini Lingala, and Vijjulatha Manga. "Docking and 3D QSAR Studies on p38α MAP Kinase Inhibitors." E-Journal of Chemistry 8, no. 4 (2011): 1596–605. http://dx.doi.org/10.1155/2011/184863.

Full text

Abstract:

The p38 signaling cascade has emerged as an attractive target for the design of novel chemotherapeutic agents for the treatment of inflammatory diseases. Three dimensional quantitative structure- activity relationship (3D- QSAR) studies were performed on a series of 25, 2-aminothiazole analogs as inhibitors of p38α mitogen activated protein (MAP) kinase. The docking results provided a reliable conformational alignment scheme for the 3D-QSAR model. The 3D-QSAR model showed very good statistical results namely q2, r2and r2predvalues for both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models & docking results provided the most significant correlation of steric, electrostatic, hydrophobic,H-bond donor,H-bond acceptor fields with biological activities and the provided values were in good agreement with the experimental results. The information rendered from molecular modeling studies gave valuable clues to optimize the lead and design new potential inhibitors.

APA, Harvard, Vancouver, ISO, and other styles

17

Sudhana, Saddala Madhu, and Pradeepkiran Jangampalli Adi. "Synthesis, Biological Evaluation and Molecular Docking Studies of Novel Di-hydropyridine Analogs as Potent Antioxidants." Current Topics in Medicinal Chemistry 19, no. 29 (December 26, 2019): 2676–86. http://dx.doi.org/10.2174/1568026619666191105100959.

Full text

Abstract:

Aims: The aim of this study is to synthesize, characterize and biological evaluation of 3-ethyl 5- methyl2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate derivatives. Background: An efficient synthesis of two series of novel carbamate and sulfonamide derivatives of amlodipine, 3-ethyl 5-methyl 2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (amlodipine) 1 were chemical synthesized process. Materials & Methods: In this process, various chloroformates 2(a-e) and sulfonyl chlorides 4(a-e) on reaction with 1 in the presence of N,N–dimethylpiperazine as a base in THF at 50-550 oC, the corresponding title compounds 3(a-e) and 5(a-e) in high yields. Furthermore, the compounds 3(a-e) and 5(a-e) were evaluated for antioxidant activity (DPPH method), metal chelating activity, hemolytic activity, antioxidant assay (ABTS method), cytotoxicity, molecular docking and in silico ADMET properties. Result: Results revealed that 5a, 5e, 3d, 3a and 5c exhibited high antioxidant, metal chelating activities, but 5a, 5e and 3d exhibited low activity. The molecular docking studies and ADMET of suggested ligands showed the best binding energies and non-toxic properties. Conclusion: The present in silico and in vitro evaluations suggested that these dihydropyridine derivatives act as potent antioxidants and chelating agents which may be useful in treating metals induced oxidative stress associated diseases.

APA, Harvard, Vancouver, ISO, and other styles

18

Luthra, Amit, Naduni Paranagama, William Swinehart, Susan Bayooz, Phuc Phan, Vanessa Quach, Jamie M. Schiffer, Boguslaw Stec, Dirk Iwata-Reuyl, and Manal A. Swairjo. "Conformational communication mediates the reset step in t6A biosynthesis." Nucleic Acids Research 47, no. 12 (May 22, 2019): 6551–67. http://dx.doi.org/10.1093/nar/gkz439.

Full text

Abstract:

Abstract The universally conserved N6-threonylcarbamoyladenosine (t6A) modification of tRNA is essential for translational fidelity. In bacteria, t6A biosynthesis starts with the TsaC/TsaC2-catalyzed synthesis of the intermediate threonylcarbamoyl adenylate (TC–AMP), followed by transfer of the threonylcarbamoyl (TC) moiety to adenine-37 of tRNA by the TC-transfer complex comprised of TsaB, TsaD and TsaE subunits and possessing an ATPase activity required for multi-turnover of the t6A cycle. We report a 2.5-Å crystal structure of the T. maritima TC-transfer complex (TmTsaB2D2E2) bound to Mg2+-ATP in the ATPase site, and substrate analog carboxy-AMP in the TC-transfer site. Site directed mutagenesis results show that residues in the conserved Switch I and Switch II motifs of TsaE mediate the ATP hydrolysis-driven reactivation/reset step of the t6A cycle. Further, SAXS analysis of the TmTsaB2D2-tRNA complex in solution reveals bound tRNA lodged in the TsaE binding cavity, confirming our previous biochemical data. Based on the crystal structure and molecular docking of TC–AMP and adenine-37 in the TC-transfer site, we propose a model for the mechanism of TC transfer by this universal biosynthetic system.

APA, Harvard, Vancouver, ISO, and other styles

19

Roster, Colm P., Danielle LaVigne, Jillian E. Milanes, Emily Knight, Heidi D. Anderson, Sabrina Pizarro, Elijah M. Harding, et al. "Enolase Inhibitors as Early Lead Therapeutics against Trypanosoma brucei." Pathogens 12, no. 11 (October 28, 2023): 1290. http://dx.doi.org/10.3390/pathogens12111290.

Full text

Abstract:

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) was a potent enzyme inhibitor (IC50 value of 0.60 ± 0.23 µM), while a six-membered ring-bearing phosphonate, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX), was less potent (IC50 value of 2.1 ± 1.1 µM). An analog with a larger seven-membered ring, (1-hydroxy-2-oxoazepan-3-yl) phosphonic acid (HEPTA), was not active. Molecular docking simulations revealed that deoxy-SF2312 and HEX had binding affinities of −6.8 and −7.5 kcal/mol, respectively, while the larger HEPTA did not bind as well, with a binding of affinity of −4.8 kcal/mol. None of these compounds were toxic to BSF parasites; however, modification of enzyme-active phosphonates through the addition of pivaloyloxymethyl (POM) groups improved activity against T. brucei, with POM-modified (1,5-dihydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (POMSF) and POMHEX having EC50 values of 0.45 ± 0.10 and 0.61 ± 0.08 µM, respectively. These findings suggest that HEX is a promising lead against T. brucei and that further development of prodrug HEX analogs is warranted.

APA, Harvard, Vancouver, ISO, and other styles

20

Zaki, Waheed A., Selwan M. El-Sayed, Mohamed Alswah, Ahmed El-Morsy, Ashraf H. Bayoumi, Abrahman S. Mayhoub, Walaa H. Moustafa, et al. "Design, Synthesis, In Vitro, and In Silico Studies of New N5-Substituted-pyrazolo[3,4-d]pyrimidinone Derivatives as Anticancer CDK2 Inhibitors." Pharmaceuticals 16, no. 11 (November 11, 2023): 1593. http://dx.doi.org/10.3390/ph16111593.

Full text

Abstract:

CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo[3,4-d]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4-d]pyrimidinone derivatives bearing N5-2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC50 values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds 4a and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development.

APA, Harvard, Vancouver, ISO, and other styles

21

RAJALAKSHMI, RAMARAJAN, RAJAVEL SANTHI, and THANGARAJ ELAKKIYA. "Synthesis, Characterization, Biological Evaluation and Molecular Docking Studies of Some Oxazinyl-Thiazolidinone Derivatives." Asian Journal of Chemistry 32, no. 9 (2020): 2125–29. http://dx.doi.org/10.14233/ajchem.2020.22710.

Full text

Abstract:

A series of new 4-thiazolidinone derivatives of 2-(4-chlorophenyl)-3-(6-(thiophen-2-yl)-4-p-tolyl-4H-1,3-oxazin-2-yl)- thiazolidin-4-one (7h-m) are synthesized because of its wide range of biological activities.1H & 13C NMR, IR studies were applied for the elucidation of all the synthesized compounds. All the synthesized compounds have been tested for antidiabetic and antioxidant activity in vitro method against standard. The analogs 7h-m was evaluated for α-amylase and α-glucosidase inhibitory potential. The structures of all the compounds have been screened for antioxidant activity using DPPH radical scavenging assay, NO scavenging method. Molecular docking studies were accomplished in addition to understand the binding affinity of those compounds with PDBID 2HR7 which showed that the synthesized derivatives bind in the lively binding site of the target protein

APA, Harvard, Vancouver, ISO, and other styles

22

Kapoor, Neha, Tanushree Banerjee, Ponnusamy Babu, Koustav Maity, Namita Surolia, and Avadhesha Surolia. "Design, development, synthesis, and docking analysis of 2â²-substituted triclosan analogs as inhibitors forPlasmodium falciparumEnoyl-ACP reductase." IUBMB Life 61, no. 11 (November 2009): 1083–91. http://dx.doi.org/10.1002/iub.258.

Full text

APA, Harvard, Vancouver, ISO, and other styles

23

Janežič, Matej, Katja Valjavec, Kaja Bergant Loboda, Barbara Herlah, Iza Ogris, Mirijam Kozorog, Marjetka Podobnik, Simona Golič Grdadolnik, Gerhard Wolber, and Andrej Perdih. "Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα." International Journal of Molecular Sciences 22, no. 24 (December 15, 2021): 13474. http://dx.doi.org/10.3390/ijms222413474.

Full text

Abstract:

In this study, we utilized human DNA topoisomerase IIα as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore model that supplements the static structure-based-pharmacophore information with a dynamic component. Subsequently, derived pharmacophore models were employed in a virtual screening campaign of a library of natural compounds. Experimental evaluation identified flavonoid compounds with promising topoisomerase IIα catalytic inhibition and binding studies confirmed interaction with the ATPase domain. We constructed a binding model through docking and extensively investigated it with molecular dynamics MD simulations, essential dynamics, and MM-GBSA free energy calculations, thus reconnecting the new results to the initial dynophore-based screening model. We not only demonstrate a new design strategy that incorporates a dynamic component of molecular recognition, but also highlight new derivates in the established flavonoid class of topoisomerase II inhibitors.

APA, Harvard, Vancouver, ISO, and other styles

24

Marciniec, Krzysztof, Zuzanna Rzepka, Elwira Chrobak, Stanisław Boryczka, Małgorzata Latocha, Dorota Wrześniok, and Artur Beberok. "Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study." Molecules 28, no. 6 (March 9, 2023): 2509. http://dx.doi.org/10.3390/molecules28062509.

Full text

Abstract:

Cancer cells need to carefully regulate their metabolism to keep them growing and dividing under the influence of different nutrients and oxygen levels. Muscle isoform 2 of pyruvate kinase (PKM2) is a key glycolytic enzyme involved in the generation of ATP and is critical for cancer metabolism. PKM2 is expressed in many human tumors and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various modulators regulate PKM2, shifting it between highly active and less active states. In the presented work, a series of 8-quinolinesulfonamide derivatives of PKM2 modulators were designed using molecular docking and molecular dynamics techniques. New compounds were synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Compound 9a was identified in in silico studies as a potent modulator of muscle isoform 2 of pyruvate kinase. The results obtained from in vitro experiments confirmed the ability of compound 9a to reduce the intracellular pyruvate level in A549 lung cancer cells with simultaneous impact on cancer cell viability and cell-cycle phase distribution. Moreover, compound 9a exhibited more cytotoxicity on cancer cells than normal cells, pointing to high selectivity in the mode of action. These findings indicate that the introduction of another quinolinyl fragment to the modulator molecule may have a significant impact on pyruvate levels in cancer cells and provides further directions for future research to find novel analogs suitable for clinical applications in cancer treatment.

APA, Harvard, Vancouver, ISO, and other styles

25

Narasimha, M., B. Revanth, D. Mahender, and P. Sarita Rajender. "Synthesis and Molecular Docking Studies of Triazole Conjugated Novel 2,4-Disubstituted Thiazole Derivatives as CDK2 Inhibitors." Asian Journal of Chemistry 33, no. 8 (2021): 1849–54. http://dx.doi.org/10.14233/ajchem.2021.23257.

Full text

Abstract:

A series of triazole conjugated novel 2,4-disubstituted thiazole derivatives (9a-l) were synthesized from salicylaldehyde. These new chemical entities were characterized by their IR, 1H & 13C NMR, mass spectral data and their molecular docking studies were performed to identify potential inhibitors of CDK2 protein. The synthesized analogs 9a-l were docked with CDK2 protein (PDB: 1GIJ). Among these 9h, 9j and 9k showed better Glide score, Prime MM-GBSA and ADME properties as compared to seliciclib and dinaciclib cancer inhibiting drugs of CDK2 protein. The amino acid Val83 of CDK2 protein was consistently binding to new chemical entities indicating that amino acid is crucial and responsible for its inhibition. Present findings suggested that compound 9h has 100% human oral absorption with highest Glide score -8.3kcal/mol whereas drug molecules have feebler binding capacity and less Glide score indicating that the synthesized new chemical entity as potential inhibitor for CDK2 protein.

APA, Harvard, Vancouver, ISO, and other styles

26

Liu, Yong-Xuan, Shuang Gao, Tong Ye, Jia-Zhong Li, Fei Ye, and Ying Fu. "Combined 3D-quantitative structure–activity relationships and topomer technology-based molecular design of human 4-hydroxyphenylpyruvate dioxygenase inhibitors." Future Medicinal Chemistry 12, no. 9 (May 2020): 795–811. http://dx.doi.org/10.4155/fmc-2019-0349.

Full text

Abstract:

Aim: 4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as an important target against tyrosinemia type I. This paper aimed to explore the structure–activity relationship of HPPD inhibitors with pyrazole scaffolds and to design novel HPPD inhibitors. Methodology & results: The best 3D-quantitative structure–activity relationships model was established by two different strategies based on 40 pyrazole scaffold-based analogs. Screening of molecular fragments by topomer technology, combined with molecular docking, 14 structures were identified for potential human HPPD inhibitory activity. Molecular dynamics results demonstrated that all the compounds obtained bound to the enzyme and possessed a satisfactory binding free energy. Conclusion: The quantitative structure–activity relationship of HPPD inhibitors of pyrazole scaffolds was clarified and 14 original structures with potential human HPPD inhibitory activity were obtained.

APA, Harvard, Vancouver, ISO, and other styles

27

Betari, Nibal, Kristoffer Sahlholm, Yuta Ishizuka, Knut Teigen, and Jan Haavik. "Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis." Future Medicinal Chemistry 12, no. 16 (August 2020): 1461–74. http://dx.doi.org/10.4155/fmc-2020-0127.

Full text

Abstract:

Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation. Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound 1 (2-(4-methylphenyl)-1,2-benzisothiazol-3(2 H)-one), which showed high potency (50% inhibition at 98 ± 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure–activity relationships studies revealed several analogs of 1 showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of 1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed. Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.

APA, Harvard, Vancouver, ISO, and other styles

28

Gao, Kai, Wenjia Wang, Thales Kronenberger, Carsten Wrenger, and Matthew R. Groves. "The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation." Crystals 9, no. 10 (October 17, 2019): 534. http://dx.doi.org/10.3390/cryst9100534.

Full text

Abstract:

Pyridoxine/pyridoxal kinase (PdxK), belongs to the ribokinase family and is involved in the vitamin B6 salvage pathway by phosphorylating 5-pyridoxal (PL) into an active form. In the human malaria parasite, Plasmodium falciparum, PfPdxK functions to salvage vitamin B6 from both itself and its host. Here, we report the crystal structure of PfPdxK from P. falciparum in complex with a non-hydrolyzable ATP analog (AMP-PNP) and PL. As expected, the fold is retained and both AMP-PNP and PL occupy the same binding sites when compared to the human ortholog. However, our model allows us to identify a FIxxIIxL motif at the C terminus of the disordered repeat motif (XNXH)m that is implicated in binding the WD40 domain and may provide temporal control of PfPdxK through an interaction with a E3 ligase complex. Furthermore, molecular docking approaches based on our model allow us to explain differential PfPdxK phosphorylation and activation of a novel class of potent antimalarials (PT3, PT5 and PHME), providing a basis for further development of these compounds. Finally, the structure of PfPdxK provides a high-quality model for a better understanding of vitamin B6 synthesis and salvage in the parasite.

APA, Harvard, Vancouver, ISO, and other styles

29

Alagöz, Mehmet Abdullah. "New molecule design with in-silico methods for Covid-19 treatment." Bioorganic and Medicinal Chemistry Reports 3, no. 2 (December 12, 2020): 32–40. http://dx.doi.org/10.25135/acg.bmcr.23.20.08.1773.

Full text

Abstract:

Intensive studies are being conducted to develop effective prevention and treatment strategies for the Covid-19 pandemic. During a pandemic, it is vital to act quickly to develop a defense strategy. It usually takes a long time to develop a preventive vaccine, and immediate drug development is needed to reduce the impact of the rapidly increasing Covid-19 pandemic. This study aimed to design an effective and potent drug by selecting remdesivir, a nucleotide analog prodrug that inhibits viral RNA polymerases and is known to be active against Covid-19. Remdesivir is metabolized into active nucleoside triphosphate (NTP) by the host; this metabolite competes with adenosine triphosphate (ATP) for incorporation into the nascent RNA strand. Therefore, molecular docking studies have been conducted based on NTP (the active form of remdesivir), and a target molecule that could be effective against Covid-19 has been designed.

APA, Harvard, Vancouver, ISO, and other styles

30

Kassem, Asmaa F., Eman M. H. Abbas, Dina S. El-Kady, Hanem M. Awad, and Wael A. El-Sayed. "Design, Synthesis and Anticancer Activity of New Thiazole-Tetrazole or Triazole Hybrid Glycosides Targeting CDK-2 via Structure-Based Virtual Screening." Mini-Reviews in Medicinal Chemistry 19, no. 11 (July 10, 2019): 933–48. http://dx.doi.org/10.2174/1389557519666181231121217.

Full text

Abstract:

Background & Objective: The target tetrazole glycosides were synthesized by construction of ring system by cycloaddition reaction of benzothiazole-linked nitrile derivative and sodium azide followed by N-glycosylation process and deprotection. Methods: The triazole glycosides were prepared by applying click approach involving dipolar cycloaddition of benzothiazole possessing alkyne functionality and different glycosyl azides. The products incorporating acyclic analogs of sugar moieties were synthesized through alkylation using acyclic oxygenated halides. Results: The anticancer activity was studied against human breast adenocarcinoma cells (MCF-7) and human normal Retina pigmented epithelium cells (RPE-1). High activities were revealed by three compounds with IC50 values 11.9-16.5 µM compared to doxorubicin (18.6 µM) in addition to other four derivatives with good inhibition activities. Conclusion: Enzyme docking investigation was performed into cyclin-dependent kinase 2 (CDK2); a potential target for cancer medication. Compounds which have possessed highest activities revealed good fitting inside the binding site of the protein molecular surface and showed minimum binding energy.

APA, Harvard, Vancouver, ISO, and other styles

31

Qiao, Shigang, Wen-jie Zhao, Huan-qiu Li, Gui-zhen Ao, Jian-zhong An, Chen Wang, and Hui-ling Zhang. "Necrostatin-1 Analog DIMO Exerts Cardioprotective Effect against Ischemia Reperfusion Injury by Suppressing Necroptosis via Autophagic Pathway in Rats." Pharmacology 106, no. 3-4 (2021): 189–201. http://dx.doi.org/10.1159/000510864.

Full text

Abstract:

Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.

APA, Harvard, Vancouver, ISO, and other styles

32

Khan, Shah Alam, S. Monawwar Imam, Aftab Ahmad, Syed Hussain Basha, and Asif Husain. "Synthesis, molecular docking with COX 1& II enzyme, ADMET screening and in vivo anti-inflammatory activity of oxadiazole, thiadiazole and triazole analogs of felbinac." Journal of Saudi Chemical Society 22, no. 4 (May 2018): 469–84. http://dx.doi.org/10.1016/j.jscs.2017.05.006.

Full text

APA, Harvard, Vancouver, ISO, and other styles

33

Pei, ShanShan, Monica L. Guzman, Shama Nasim, Lei Shi, Peter A. Crooks, and Craig T. Jordan. "Analysis of the Anti-Leukemia Mechanism of Parthenolide." Blood 114, no. 22 (November 20, 2009): 2734. http://dx.doi.org/10.1182/blood.v114.22.2734.2734.

Full text

Abstract:

Abstract Abstract 2734 Poster Board II-710 We have previously demonstrated that parthenolide (PTL), a naturally occurring small molecule found in feverfew Chrysanthemum parthenium, induces apoptosis in primary acute myeloid leukemia (AML) cells, including the stem and progenitor cell compartment. Based on these preclinical findings, a PTL derivative (dimethylamino parthenolide) is currently being evaluated in a phase I clinical trial. However, despite the promising activity of PTL, its underlying mechanism of action remains poorly understood. Thus, we have undertaken biochemical studies to better characterize how PTL mediates leukemia-specific cell death. Chemically, the key structural feature of PTL is its alpha-metheylene-gamma-lactone moiety, which via Michael reaction is predicted to mediate potent free thiol scavenging, an activity readily observed in PTL-treated cells. Reported consequences of PTL chemical reactivity in a variety of cell types, represent a broad range of activities that include inhibition of NFkB, activation of p53, ubiquitination of MDM2, inhibition of DNMT1 and inhibition of HDAC1. To better define the specific activities responsible for parthenolide-mediated leukemia cell death, we have employed two general approaches. First, we generated a biotinylated analog of parthenolide (PTL-biotin), which was shown to retain the anti-leukemia activity of the parent compound. PTL-biotin was then used in biochemical pull-down assays to purify parthenolide target proteins, followed by liquid phase chromatography-mass spectrometry (LC-MS) for protein identification. To further verify molecular interactions, native non-biotinylated parthenolide was used to compete binding between candidate targets and PTL-biotin. These studies identified HSP70 as a direct target of PTL. Notably, cysteine-17 of HSP70 is exposed to the ADP/ATP binding site crevice and a molecular docking study indicates that the covalent attachment of PTL to this residue should disrupt the ATP hydrolysis function of the protein. These findings imply that inhibition of HSP70 may contribute to the cell death mechanism underlying PTL anti-leukemia based activity. As a second approach to characterizing PTL, we have performed comparative studies using the closely related compound costunolide (CSN). Since previous structure-activity studies with PTL analogs revealed that opening of the epoxide ring at C4-C5 of the molecule completely destroys the anti-tumor activity, we sought to utilize a compound lacking this feature. CSN lacks the epoxide group, but is otherwise identical to PTL, and retains the key alpha-metheylene-gamma-lactone moiety. Interestingly, at concentrations where PTL is highly cytotoxic, CSN does not induce leukemia-specific cell death (less than 10% death for primary AML cells at 7.5 microM). Analysis of CSN activity demonstrated that despite the lack of AML cell death, CSN still induced loss of free thiols and increased reactive oxygen species in a fashion comparable to PTL (as measured by mBBR and CM-H2DCFDA based flow cytometry). However, CSN is markedly less effective as an inhibitor of NFkB activity (measured by phosphorylation level of NFkB p65). Taken together these findings indicate that oxidative stress alone is not sufficient for PTL-mediated cell death, and further extend previous molecular genetic data demonstrating that NFkB inhibition is an important component of the overall cell death mechanism. The data also show that the alpha-metheylene-gamma-lactone moiety alone is not sufficient to mediate all aspects of PTL activity, and that at least some activity/specificity is created by juxtaposition of the epoxide group. Based on these studies, as well as previous data, we propose that inhibition of NFkB and HSP70 are components of the parthenolide-mediated cell death mechanism, and that oxidative stress is a necessary but not sufficient aspect of its leukemia-specific activity. Disclosures: No relevant conflicts of interest to declare.

APA, Harvard, Vancouver, ISO, and other styles

34

Choudhary, Dhiraj Kumar, Navaneet Chaturvedi, Amit Singh, and Abha Mishra. "Investigation of hypoglycemic effects, oxidative stress potential and xanthine-oxidase activity of polyphenols (gallic acid, catechin) derived from faba bean on 3T3-L1 cell line: insights into molecular docking and simulation study." Toxicology Research 9, no. 3 (May 21, 2020): 308–22. http://dx.doi.org/10.1093/toxres/tfaa025.

Full text

Abstract:

Abstract Hypoglycemic potential and xanthine-oxidase (XO) activity of polyphenols from faba bean were evaluated in the 3T3-L1 cell line, and an interaction study in silico with XO was performed with considerable bioactive components of acetone extract of faba beans. The protonated and fragmented behavior of acetone seed extract revealed the presence of gallic acid (MS/MS, m/z 169) and catechin (MSn, m/z 288.3). Flow cytometry study explained the effect of hydrogen peroxide (H2O2) on cell line as cell death was increased from 9.72 to 41.66% as compared to the control (without H2O2). The atomic force microscopy (AFM), scanning electron microscopy and reactive oxygen species measurement also confirmed the protective effect of polyphenols in the 3T3-L1 cell lines. Oxidative stress through propidium iodide and 4′,6-diamidino-2-phenylindole staining demonstrated that the apoptotic ratio was 0.35 ± 2.62 (P < 0.05) and 30 ± 2.54% in H2O2-treated cells, respectively, as compared to control. The observations of flow cytometry and confocal microscopy marked the effect of seed extract (0.86 ± 0.031, 3.52 ± 0.52, P < 0.05), on glucose uptake in cells through the better relative fluorescence intensity than that of the control. Moreover, molecular docking and molecular dynamics simulation studies gave an insight into the predicted residues that hold favorable polyphenolic-specific interactions. The probable binding modes of the gallic acid and catechin from this study may extend the knowledge of the XO-polyphenol interactions and offered the way to design the analogs of acetone seed extract with reduced toxicity.

APA, Harvard, Vancouver, ISO, and other styles

35

Pradhan, Joohee, and Sunita Panchawat. "Molecular Docking Studies and Pharmacophore Modeling of Some Insulin Mimetic Agents from Herbal Sources: A Rational Approach towards Designing of Orally Active Insulin Mimetic Agents." Current Traditional Medicine 6, no. 2 (February 27, 2020): 121–33. http://dx.doi.org/10.2174/2215083805666191001220342.

Full text

Abstract:

Background:: Many herbal drugs have been found to possess oral insulin mimetic property as evidenced from the literature. Although, to date there is no efficient, synthetic orally active insulin-mimetic drug available clinically. Computer-Aided Drug Design (CADD) may help in the development of such agents through Pharmacophore modeling. Objective:: The present work is aimed at the In-silico designing of Pharmacophore that defines the structural requirements of a molecule to possess oral insulin-mimetic properties. Methods:: A set of 16 orally active insulin-mimetic natural compounds available through literature was used to develop a structure-based pharmacophore in a “three-step filtration process” comprised of Lipinski’s rule of 5, Minimum binding energy with the receptor and Ghose filter to the Lipinski’s rule for oral bioavailability of the drugs. The selected ligands were docked with phosphorylated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog (PDB ID: 1IR3) using Autodock 4.2 and their interaction with the receptor was analyzed followed by the generation of shared and merged feature pharmacophore by Ligandscout 4.2.1. Results:: There are three important structural features that contribute to interaction with the active site of the insulin receptor: these are hydrogen bond donor groups, hydrogen bond acceptor groups and hydrophobic interactions. It is important to note that positive or negative ionizable groups or the presence of aromatic rings are not important for the activity. Conclusion:: Taking a clue from the developed pharmacophore, one may design new lead having necessary groups required for the insulin-mimetic activity that can be elaborated synthetically to get a series of compounds with possible oral insulin-mimetic activity.

APA, Harvard, Vancouver, ISO, and other styles

36

Dandamudi, Akhila, William Seibel, Huzoor Akbar, and Yi Zheng. "Structure-Activity Relationship Analysis of Analogs of Rhosin, a RhoA Inhibitor, Reveals a New Generation of Improved Antiplatelet Agents." Blood 138, Supplement 1 (November 5, 2021): 3989. http://dx.doi.org/10.1182/blood-2021-153108.

Full text

Abstract:

Abstract Platelet activation and aggregation play a key role in mediating hemostasis and thrombosis. The antiplatelet therapies currently available in the market are associated with a high risk of hemorrhage and are mostly irreversible in suppressing platelet activity; hence, there is a need to develop better therapeutic agents. Previous genetic and pharmacological studies have implicated the small GTPase RhoA in multiple platelet signaling pathways. We devised a lead RhoA activity-specific inhibitor, Rhosin/G04, based on the structure-function relationship of RhoA interaction with its activator, guanine nucleotide exchange factor (GEF) (Figure 1A). Rhosin/G04 binds to RhoA directly with micromolar affinity at a surface groove that is essential for GEF recognition and blocks GEF-mediated GTP loading to RhoA. Rhosin/G04 inhibits platelet spreading on fibrinogen and thrombin-induced platelet aggregation, mimicking effects of RhoA gene targeting. In the current work, we have utilized the inhibitory activity of G04 for platelet activation and its biochemical activity to define its structure-activity relationship (SAR) and to understand its mechanism of action in an effort to improve efficacy and druggability. The structure of G04 in a groove of RhoA interaction was hypothesized based on the docking studies using Molsoft ICM-Pro. Cincinnati Children's Hospital Medical Center's compound library of over 360,000 chemicals was scanned for G04 analogs by similarity and substructure searches. In the initial screen, a human platelet aggregation assay was performed at both a low concentration (1 µg/ml) and a high concentration (5 µg/ml) of collagen. The first round similarity search resulted in a set of 7 compounds (Set-1), from which, compound 177629 showed significantly enhanced potency relative to G04 (Figure 1B). The second round of similarity searches for compounds more closely related to 177629 (Set-2) identified 14 compounds. The third-round search for other related compounds (Set-3) led to 9 additional compounds that add to the understanding of the SAR. The compounds that showed enhanced antiplatelet activity were examined for their potency and selectivity in in vitro biochemical binding assays and in suppressing RhoA-GTP formation and downstream phosphorylation of myosin light chain (p-MLC) signaling in platelets. The active compounds were further examined for their anti-platelet activities under diverse stimuli including thrombin, ADP, U46619 (a stable thromboxane receptor agonist), and arachidonic acid. The most active compounds from Set-1, Set-2, and Set-3 inhibited platelet aggregation by at least 70% and showed IC 50 values below 6 µM. Of these compounds, 12 showed significantly greater potency than the initial compound, G04. The most active compounds were 177618, 177619, 177628, 177629, 177633, and 177634. These compounds specifically inhibited RhoA activity and blocked p-MLC. SAR analyses led us to believe that the quinoline is optimally attached to the hydrazine at the 4-position. The halogen (choloro- or trifluoromethyl-) substitution at the 7- or 8- position improved activity, and the 7- position may be slightly favored. The aryl group is considerably variable with similar potency between the indole, methylphenyl, and dichlorophenyl- groups. Rhosin/G04 is the R enantiomer (i.e. Rhosin is R-G04), so its S enantiomer, S-G04 was also evaluated (Figure 1C). S-G04 is significantly more potent than R-G04 in inhibiting collagen-stimulated RhoA-GTP formation and aggregation of platelets, and its effect is completely reversible by washing the platelets. Finally, R-G04 and S-G04 showed differential inhibition of arachidonic acid and U46619 stimulated primary and secondary aggregation, highlighting the potential utilities of the inhibitors in dissecting different platelet activation mechanisms. S-G04 is active in inhibiting thrombin, ADP, U46619, and arachidonic acid-mediated platelet activation at submicromolar concentration, suggesting a broad role of RhoA signaling in integrating platelet signal cross talk. In summary, evaluation of Rhosin/R-G04 analogs in a platelet activity screen identified a new generation of improved small-molecule RhoA inhibitors, including an enantiomer with significantly improved efficacy. These analog studies of novel anti-platelet agents provide a new approach to effectively and reversibly manipulate platelet activities. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

APA, Harvard, Vancouver, ISO, and other styles

37

Wang, Zhiguo, Robert J. Sheaff, and Syed R. Hussaini. "Chloroquine-Based Mitochondrial ATP Inhibitors." Molecules 28, no. 3 (January 24, 2023): 1161. http://dx.doi.org/10.3390/molecules28031161.

Full text

Abstract:

Mitochondria is an important drug target for ailments ranging from neoplastic to neurodegenerative diseases and metabolic diseases. Here, we describe the synthesis of chloroquine analogs and show the results of mitochondrial ATP inhibition testing. The 2,4-dinitrobenzene-based analogs showed concentration-dependent mitochondrial (mito.) ATP inhibition. The most potent mito. ATP inhibitor was found to be N-(4-((2,4-Dinitrophenyl)amino)pentyl)-N-ethylacetamide (17).

APA, Harvard, Vancouver, ISO, and other styles

38

Liu, Ming, Lei Wang, Xiao Li Liu, and Wen Xiang Hu. "Study of Molecular Docking of Mu Opioid Receptor Agonist - Fentanyl and its Analogs Based on Docking." Advanced Materials Research 655-657 (January 2013): 1931–34. http://dx.doi.org/10.4028/www.scientific.net/amr.655-657.1931.

Full text

Abstract:

The interaction mechanism of a series of fentanyl analogs are examined using molecular docking to the mu-opioid receptor based on Surflex-Docking. Fully automatic flexible molecular docking (Surflex-Docking) was performed by using the possible active conformations of 70 fentanyl analogs and optimized 3D structure of mu-opioid receptor. The site mainly consist of residues ILE 109, ASP 112, TYR113, MET116, HIS262, TYR291. All these residues take part in interaction between fentanyl and mu-opioid receptor. Meanwhile, the results provide new insight to design of experiments aimed at understanding the structure.

APA, Harvard, Vancouver, ISO, and other styles

39

Choudary, Jayant, Suvarna G. Kini, Sreedhara Ranganath Pai Karkala, and Muhammad Mubeen. "Docking Studies and Biological Activity of Fosinopril Analogs." International Journal of Medicinal Chemistry 2014 (July 6, 2014): 1–5. http://dx.doi.org/10.1155/2014/721834.

Full text

Abstract:

The purpose of the present study was to determine the angiotensin-I converting enzyme inhibitory activity of few novel Fosinopril derivatives which were predicted to possess better ACE inhibitory activity and lesser side effects than the existing drug molecule. In vitro study was carried out to determine ACE inhibitory activity of six different Fosinopril analogs by spectrophotometric assay procedure. Analog A2 showed the highest activity compared to other analogs and as well as Fosinopril itself. Docking studies of the compounds were done with the help of VLife MDS 3.0 software using GRIP batch docking method to find out which derivative had a better docking with ACE. The compounds which showed the highest negative score in docking have also exhibited good ACE inhibitory activity.

APA, Harvard, Vancouver, ISO, and other styles

40

Joseph, Sheldon M., Matthew A. Pifer, Ronald J. Przybylski, and George R. Dubyak. "Methylene ATP analogs as modulators of extracellular ATP metabolism and accumulation." British Journal of Pharmacology 142, no. 6 (July 2004): 1002–14. http://dx.doi.org/10.1038/sj.bjp.0705865.

Full text

APA, Harvard, Vancouver, ISO, and other styles

41

Arsianti, Ade, Fadilah Fadilah, Linda Erlina, and Rafika Indah Paramita. "MOLECULAR DOCKING OF ANTIMYCIN A3 ANALOGS AND ITS AROMATIC SEGMENTS AS INHIBITORS OF APOPTOSIS PROTEIN MARKER BCL-XL AND MCL-1." Asian Journal of Pharmaceutical and Clinical Research 10, no. 8 (August 1, 2017): 317. http://dx.doi.org/10.22159/ajpcr.2017.v10i8.18165.

Full text

Abstract:

Objective: Apoptosis is an important cellular process that causes the death of damaged cells. Its malfunction can lead to cancer development and poor response to conventional chemotherapy. Cellular proteins from the B-cell lymphoma 2 (BCL-2) family are crucial for apoptosis. Breast cancer is the most commonly diagnosed cancer among women worldwide. The aim of this work was to design using in silico docking antimycin A3, antimycin analogs, and its aromatic segments as inhibitors of Bcl-xl and Mcl-1.Methods: In silico molecular docking approach has been utilized to find the potential anticancer from antimycin A3 analogs and its aromatic segments. Antimycin A3 analogs and its aromatic segments were modeled into three-dimensional (3D) structures using Marvin Sketch. Based on Protein Data Bank, 3ZLN for Bcl-xl, and 5IEZ for Mcl-1 were selected as apoptosis protein marker from BCL-2 family. Geometry optimization and minimization of energy 3D structure of antimycin A3 analogs and segments (ligands) using the AutoDock software. Docking process and amino acid residue analysis were executed using AutoDock software. The best docking score was shown by the lowest binding energy and also checked with Lipinski rule of five.Results: In silico molecular docking showed antimycin A3 analogs, amide 5 and aromatic segment 14 have the best interaction and activity for Bcl-xl receptor inhibition. Moreover, amide 5 and segment 15 showed the best interaction and activity for Mcl-1 receptor inhibition.Conclusion: Our results clearly demonstrate that amide 5, segment 14, and segment 15 of antimycin A3 analog have a strong inhibitory activity against Bcl-xl and Mcl-1, and should be further developed as a promising candidate for the new anti-apoptosis agents.

APA, Harvard, Vancouver, ISO, and other styles

42

Martins, Lucas Sousa, Reinaldo W. A. Gonçalves, Joana J. S. Moraes, Cláudio Nahum Alves, and José Rogério A. Silva. "Computational Analysis of Triazole-Based Kojic Acid Analogs as Tyrosinase Inhibitors by Molecular Dynamics and Free Energy Calculations." Molecules 27, no. 23 (November 23, 2022): 8141. http://dx.doi.org/10.3390/molecules27238141.

Full text

Abstract:

Molecular docking, molecular dynamics (MD) simulations and the linear interaction energy (LIE) method were used here to predict binding modes and free energy for a set of 1,2,3-triazole-based KA analogs as potent inhibitors of Tyrosinase (TYR), a key metalloenzyme of the melanogenesis process. Initially, molecular docking calculations satisfactorily predicted the binding mode of evaluated KA analogs, where the KA part overlays the crystal conformation of the KA inhibitor into the catalytic site of TYR. The MD simulations were followed by the LIE method, which reproduced the experimental binding free energies for KA analogs with an r2 equal to 0.97, suggesting the robustness of our theoretical model. Moreover, the van der Waals contributions performed by some residues such as Phe197, Pro201, Arg209, Met215 and Val218 are responsible for the binding recognition of 1,2,3-triazole-based KA analogs in TYR catalytic site. Finally, our calculations provide suitable validation of the combination of molecular docking, MD, and LIE approaches as a powerful tool in the structure-based drug design of new and potent TYR inhibitors.

APA, Harvard, Vancouver, ISO, and other styles

43

Ibrahim, Mahmoud A. A., Doaa G. M. Mahmoud, Alaa H. M. Abdelrahman, Khlood A. A. Abdeljawaad, Gamal A. H. Mekhemer, Tamer Shoeib, Mohamed A. El-Tayeb, Peter A. Sidhom, Paul W. Paré, and Mohamed-Elamir F. Hegazy. "Benzothiazinone analogs as Anti-Mycobacterium tuberculosis DprE1 irreversible inhibitors: Covalent docking, validation, and molecular dynamics simulations." PLOS ONE 19, no. 11 (November 25, 2024): e0314422. http://dx.doi.org/10.1371/journal.pone.0314422.

Full text

Abstract:

Mycobacterium tuberculosis is a lethal human pathogen, with the key flavoenzyme for catalyzing bacterial cell-wall biosynthesis, decaprenylphosphoryl-D-ribose oxidase (DprE1), considered an Achilles heal for tuberculosis (TB) progression. Inhibition of DprE1 blocks cell wall biosynthesis and is a highly promising antitubercular target. Macozinone (PBTZ169, a benzothiazinone (BTZ) derivative) is an irreversible DprE1 inhibitor that has attracted considerable attention because it exhibits an additive activity when combined with other anti-TB drugs. Herein, 754 BTZ analogs were assembled in a virtual library and evaluated against the DprE1 target using a covalent docking approach. After validation of the employed covalent docking approach, BTZ analogs were screened. Analogs with a docking score less than –9.0 kcal/mol were advanced for molecular dynamics (MD) simulations, followed by binding energy evaluations utilizing the MM-GBSA approach. Three BTZ analogs–namely, PubChem-155-924-621, PubChem-127-032-794, and PubChem-155-923-972– exhibited higher binding affinities against DprE1 compared to PBTZ169 with ΔGbinding values of –77.2, –74.3, and –65.4 kcal/mol, versus –49.8 kcal/mol, respectively. Structural and energetical analyses were performed for the identified analogs against DprE1 throughout the 100 ns MD simulations, and the results demonstrated the great stability of the identified BTZ analogs. Physicochemical and ADMET characteristics indicated the oral bioavailability of the identified BTZ analogs. The obtained in-silico results provide promising anti-TB inhibitors that are worth being subjected to in-vitro and in-vivo investigations.

APA, Harvard, Vancouver, ISO, and other styles

44

Nuñez, María, Yaowei Wang, Eugenia Russinova, Ana Estévez-Braun, Angel Amesty, Andrés F. Olea, Marco Mellado, Katy Díaz, and Luis Espinoza Catalán. "Synthesis, Biological Activity, and Molecular-Docking Studies of New Brassinosteroid Analogs." International Journal of Molecular Sciences 25, no. 18 (September 21, 2024): 10158. http://dx.doi.org/10.3390/ijms251810158.

Full text

Abstract:

Much work has been dedicated to the quest to determine the structure–activity relationship in synthetic brassinosteroid (BR) analogs. Recently, it has been reported that analogs with phenyl or benzoate groups in the alkyl chain present activities comparable to those shown by natural BRs, depending on the nature of the substituent in the aromatic ring. However, as it is well known that the activity depends on the structure of the whole molecule, in this work, we have synthesized a series of compounds with the same substituted benzoate in the alkyl chain and a hydroxyl group at C3. The main goal was to compare the activities with analogs with -OH at C2 and C3. Additionally, a molecular-docking study and molecular dynamics simulations were performed to establish a correlation between the experimental and theoretical results. The synthesis of eight new BR analogs was described. All the analogs were fully characterized by spectroscopical methods. The bioactivity of these analogs was assessed using the rice lamina inclination test (RLIT) and the inhibition of the root and hypocotyl elongation of Arabidopsis thaliana. The results of the RLIT indicate that at the lowest tested concentration (1 × 10−8 M), in the BR analogs in which the aromatic ring was substituted at the para position with methoxy, the I and CN substituents were more active than brassinolide (50–72%) and 2–3 times more active than those analogs in which the substituent group was F, Cl or Br atoms. However, at the highest concentrations, brassinolide was the most active compound, and the structure–activity relationship changed. On the other hand, the results of the A. thaliana root sensitivity assay show that brassinolide and the analogs with I and CN as substituents on the benzoyl group were the most active compounds. These results are in line with those obtained via the RLIT. A comparison of these results with those obtained for similar analogs that had a hydroxyl group at C2 indicates the importance of considering the whole structure. The molecular-docking results indicate that all the analogs adopted a brassinolide-like orientation, while the stabilizing effect of the benzoate group on the interactions with the receptor complex provided energy binding values ranging between −10.17 and −13.17 kcal mol−1, where the analog with a nitrile group was the compound that achieved better contact with the amino acids present in the active site.

APA, Harvard, Vancouver, ISO, and other styles

45

Astuti, Endang, Tri Joko Raharjo, Putra Boang Manalu, Ilham Satria Putra, Stephanus Satria Waskitha, and Junita Solin. "Synthesis, Molecular Docking, and Evaluation of Some New Curcumin Analogs as Antimalarial Agents." Indonesian Journal of Chemistry 21, no. 2 (March 11, 2021): 452. http://dx.doi.org/10.22146/ijc.57646.

Full text

Abstract:

This research involves the synthesis, antimalarial evaluation, and molecular docking of several curcumin analogs. A total of six curcumin analog compounds were synthesized using aldol condensation using hydrochloric acid and sodium hydroxide catalysts. The synthesized compounds were elucidated using FTIR, 1H-NMR, 13C-NMR, and LC-MS/MS. Subsequently, all curcumin analogs were tested as an antimalarial agent against Plasmodium falciparum 3D7 strain, and their mechanism of action was evaluated through a molecular docking study. Six curcumin analogs, i.e. 2,6-bis(2-hydroxybenzylidene)cyclohexanone; 2,6-bis(2-hydroxybenzylidene)cyclopentanone; 1.5-bis(2-hydroxyphenyl)penta-1,4-diene-3-one; 2,6-bis(3-hydroxybenzylidene)cyclo-hexanone; 2,6-bis(3-hydroxybenzylidene)cyclopentanone; and 1,5-bis(3-hydroxy-phenyl)penta-1,4-diene-3-one have been successfully synthesized. In addition, 2,6-bis(2-hydroxybenzylidene) cyclopentanone demonstrated the lowest IC50 value and binding affinity of 0.04 µM and -7.6 kcal/mol, respectively. Based on molecular docking studies, this compound also showed the most potent antimalarial activity targeted at PfATP6.

APA, Harvard, Vancouver, ISO, and other styles

46

Katari, Naresh Kumar, Rambabu Gundla, Phani Kumar Reddy, Anuradha Vanam, Aruna Talatam, Noboru Motohashi, and Rao Gollapudi. "Molecular Docking Studies of Glabrene and Human Epidermal Growth Factor Receptor Kinase." INNOSC Theranostics and Pharmacological Sciences 4, no. 1 (April 29, 2022): 38–49. http://dx.doi.org/10.36922/itps.v4i1.56.

Full text

Abstract:

Background: Human epidermal growth factor receptor 2 (Her2) gene located in human chromosome17, encodes Her2 tyrosine kinase protein, and is overexpressed in breast cancer cells. Her2 is activated on phosphorylation of tyrosine by adenosine triphosphate (ATP). Nonetheless, Her2 excessively partakes in the development and prognosis of specific types of aggressive breast cancers. Therefore, Her2 inhibition therapy is primary target for the treatment of aggressive breast cancer. At present, lapatinib is one of the Food and Drug Administration approved Her2 inhibitors used in cancer therapy. In molecular docking process, glabrene with slightly higher binding energy competitively bound to the active receptor site comparable to lapatinib and ATP. Therefore, glabrene could emerge as a potential candidate for restricting Her2 overexpressed breast cancer. Objective: The present study aimed to demonstrate the inhibitory activity of glabrene, an isoflavene and xenoestrogen found in liquorice root, along with known Her2 inhibitor, lapatinib. Methods: ATP, lapatinib, and glabrene were docked on human Her2 protein 3D structure which revealed glabrene as a competitive Her2 inhibitor akin to lapatinib. Results: The docking results suggested the binding site similarities of ATP, lapatinib, and glabrene. The binding energies of docked ATP, lapatinib, and glabrene complexes with Her2 were −9.1 kcal/mol, −10.5 kcal/mol, and −11.3 kcal/mol, respectively. Conclusion: The in silico docking simulation of ATP, lapatinib, and glabrene suggested that glabrene is likewise a competitive Her2 inhibitor.

APA, Harvard, Vancouver, ISO, and other styles

47

Gendaszewska-Darmach, Edyta, Maria Maszewska, Małgorzata Zakłos, and Maria Koziołkiewicz. "Degradation of extracellular nucleotides and their analogs in HeLa and HUVEC cell cultures." Acta Biochimica Polonica 50, no. 4 (December 31, 2003): 973–84. http://dx.doi.org/10.18388/abp.2003_3627.

Full text

Abstract:

The use of nucleotides and their analogs in the pharmacological studies of nucleotide receptors (P2 class) should be preceded by detailed studies on their degradation connected with ecto-enzymes of a given cell type. In the present studies we have analyzed stability of some phosphorothioate and phosphonate analogs of ATP and ADP in the HeLa epitheloid carcinoma and endothelial HUVEC cells cultures. Our studies have revealed that ecto-nucleotide pyrophosphatase (E-NPP) is one of the main enzymes involved in the extracellular degradation of ATP and other nucleotides in the HeLa cells. On the other hand, the ecto-ATPDase is responsible for the hydrolysis of extracellular nucleotides in human endothelial cell cultures, while the E-NPP-like enzymes of the HUVEC cells are not essential to this degradation. The concerted action of the aforementioned ecto-enzymes and nucleotide pyrophosphatase, 5'-nucleotidase and adenosine deaminase present in fetal bovine serum (FBS) supplied to the culture medium, results in partial or complete degradation of the phosphorothioate (ATPgammaS) and phosphonate analogs of adenosine nucleotides (alpha,beta-methylene-ATP and beta,gamma-methylene-ATP) in the cell cultures. Only ADPbetaS appears to be resistant to these enzymes. The influence of some nucleotides and their analogs on the proliferation of the HeLa cells in presence or absence of FBS is also discussed.

APA, Harvard, Vancouver, ISO, and other styles

48

Wu, Joseph M., Stanley J. Wertheimer, Behruz Eslami, Joanne C. Figuereido, and Biswendu B. Goswami. "Some properties of 2-5A binding/nucleolytic activities in gel filtered rabbit reticulocyte lysates." Bioscience Reports 5, no. 12 (December 1, 1985): 1041–51. http://dx.doi.org/10.1007/bf01119625.

Full text

Abstract:

Rabbit reticulocyte lysates, gel filtered on Sephadex G-25 with or without ATP (or its analogs), were preincubated at 37°C and their subsequent binding to p3A4,3′-[32P]pCp was studied. Lysates filtered without ATP or in the presence of 0.1 mM 8-bromo-ATP, 1,N6-etheno-ATP, or ITP showed a time-dependent decrease in binding activity. This decrease was completely prevented when lysates were filtered with 0.1 mM ATP, 2′-deoxy-ATP, β-γ-methylene-ATP, or ATP-γ-S. The stability of binding provided by ATP or 2′-deoxy-ATP analogs corresponds to a more active 2–5A dependent endonucleolytic (RNAase L) activity based on studies using [3H] viral mRNA. Chromatography on heparin-agarose showed that ATP-supplemented gel-filtered reticulocyte lysates had a different p3A4,3′-[32P]pCp binding activity elution-profile than lysates gel-filtered in the absence of ATP. Covalent cross-linking of periodate-oxidized p3A4,3′-[32P]pC to gelfiltered lysates, preincubated at 0°C or 37°C for 30 min, showed the following results: (1) all lysates gave a major cross-linking of the radioactive ligand to an 80 000 dalton polypeptide, regardless of the temperature of preincubation, (2) Iysates gel-filtered without ATP, with 0.1 mM ITP, or β-γ-methylene-ATP, showed a significant reduction in the cross-linking of the 80 000 dalton protein, after preincubation at 37°C for 30 min. This decrease was accompanied by an increase in the labeling of two smaller polypeptides.

APA, Harvard, Vancouver, ISO, and other styles

49

Tanase, Constantin I., Lucia Pintilie, and Elena Mihai. "A Molecular Docking of New 9β-Halogenated Prostaglandin Analogs with an Ester Group at C-6 Atom of the α-Side Chain." Revista de Chimie 71, no. 4 (May 5, 2020): 101–10. http://dx.doi.org/10.37358/rc.20.4.8048.

Full text

Abstract:

Prostaglandins with cytoprotective activity were studied for a long time and a few PGE1 and PGE2 stable analogs were promoted as drugs: arbaprostil, enprostil, misoprostol and rioptostol. Nocloprost, a 9β-chlorine prostaglandin analog, has been also promoted as a cytoprotective drug; the succes with this compound stimulated the reserches, and many 9β- or 11β-substituted prostaglandins were synthesized and studied for their biological activity. In the same dirrection we previously synthesized new 9β-halogenated prostaglandins having also an ester group at the carbon atom 6. These compounds were now used in a molecular docking study to predict their potential cytoprotective (anti-ulcer) activity. The study has been done with CLC Drug Discovery Workbench 2.4. software and an oxidoreductase enzyme receptor, chosen from the Protein Data Bank, ID: 4KEW. Two recognized drugs, omeprazole (co-crystallized with the enzyme) and nocloprost were used as standard in the study. The 9β-halogenated prostaglandin analogs were finally docked. Nocloprost and all 9β-halogenated compounds had docking score greater than that of omeprazole. The majority of the 9β-halogenated analogs have a docking score even greater than that of nocloprost, indicating that these compounds could have potential cytoprotective activity. Correlations between docking score and substituents on the prostaglandin skeleton have been done.

APA, Harvard, Vancouver, ISO, and other styles

50

Katchanov, G., J. Xu, A. Clay, and A. Pelleg. "Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. IV. Role of LV vagal afferents." American Journal of Physiology-Heart and Circulatory Physiology 272, no. 4 (April 1, 1997): H1898—H1903. http://dx.doi.org/10.1152/ajpheart.1997.272.4.h1898.

Full text

Abstract:

The negative chronotropic action and the time to peak effect (t(p)) of ATP and its related analogs [2-methylthio-ATP (2-MeSATP), alpha,beta-methylene-ATP (alpha,beta-mATP), and beta,gamma-methylene-ATP (beta,gamma-mATP)] as well as ADP, AMP, and adenosine were determined in anesthetized dogs. Intra-right atrium (RA) and intra-left main coronary artery (LM) ATP markedly suppressed sinus node automaticity. ATP induced a much greater response when administered into the LM than into the RA. The t(p) of ATP administered at the former site was much shorter than that at the latter site. Intra-LM adenosine had either no effect or a relatively very small effect, and its t(p) was significantly longer than that of intra-LM ATP. Bilateral cervical vagotomy either abolished or markedly attenuated the effect of intra-RA and intra-LM ATP; under these conditions, the actions of ATP and adenosine and their t(p) values became similar. The structure-function cascade of intra-LM ATP and its analogs was alpha,beta-mATP > 2-MeSATP > ATP > or = beta,gamma-mATP > ADP >> AMP = 0. The P2X-purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid markedly attenuated the negative chronotropic action of all purine nucleotides. It was concluded that 1) ATP triggers a cardiocardiac vagal depressor reflex by stimulating vagal afferent nerve terminals in the LV myocardium and 2) this action is mediated by P2X-purinoceptors.

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Docking of ATP analogs'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles