Journal articles on the topic 'Small inhibitory compounds'
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1
Alvarez-Gonzalez, Juan Antonio, Robert Maul, Rahul M. Kohli, and Patricia J. Gearhart. "Small molecule inhibitors of Activation-Induced Deaminase." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 48.18. http://dx.doi.org/10.4049/jimmunol.200.supp.48.18.
Abstract:
Abstract Activation-Induced Deaminase (AID) is a cytosine deaminase that converts cytosine into uracil in DNA, which initiates a cascade of mutagenic DNA repair to introduce point mutations and double-strand breaks. Specific targeting of AID to the immunoglobulin heavy chain locus promotes somatic hypermutation in antibody variable genes for affinity maturation, and breaks in switch regions for class switch recombination (CSR). However, mis-targeting of AID to other loci could initiate tumor development and lead to greater drug resistance among cancer cells when continually expressed. To identify a small molecule inhibitor of AID, we screened ~400,000 compounds in conjunction with the NCATS core facility at NIH. Using FRET based analysis of cytosine deamination, we identified 150 potential inhibitors of AID catalytic activity. To confirm biological function, we examined their effects on CSR in an in vitro murine B-cell activation assay using CH12 cells, wherein 30 were confirmed inhibitor candidates. We then selected the top seven molecules to proceed with further characterization in wild type primary splenocytes, and found two near-identical compounds that had inhibitory activity. From these structures, we tested commercially available analogues and identified two molecules with inhibitory efficacy in the nanomolar range. Using these approaches, we hope to identify a small molecule with great efficacy and low toxicity for use as a molecular probe to further characterize AID’s intricacies, or even as a therapeutic agent.
2
Yan, Hua, Tomoko Chiba Mizutani, Nobuhiko Nomura, Tadakazu Takakura, Yoshihiro Kitamura, Hideka Miura, Masako Nishizawa, Masashi Tatsumi, Naoki Yamamoto, and Wataru Sugiura. "A Novel Small Molecular Weight Compound with a Carbazole Structure That Demonstrates Potent Human Immunodeficiency Virus Type-1 Integrase Inhibitory Activity." Antiviral Chemistry and Chemotherapy 16, no. 6 (December 2005): 363–73. http://dx.doi.org/10.1177/095632020501600603.
Abstract:
The integration of reverse transcribed proviral DNA into a host genome is an essential event in the human immunodeficiency virus type 1 (HIV-1) replication life cycle. Therefore, the viral enzyme integrase (IN), which plays a crucial role in the integration event, has been an attractive target of anti-retroviral drugs. Several IN inhibitory compounds have been reported previously, yet none has been successful in clinical use. To find a new, more successful IN inhibitor, we screened a diverse library of 12000 small molecular weight compounds randomly by in vitro strand-transfer assay. We identified a series of substituted carbazoles that exhibit strand-transfer inhibitory activity at low micromolar concentrations. Of these, the most potent compound exhibited an IC50 of 5.00 ±3.31 μM (CA-0). To analyse the structural determinants of strand-transfer inhibitory activity of the carbazole derivatives, we selected 23 such derivatives from our compound library and performed further analyses. Of these 23 compounds, six showed strong strand-transfer inhibition. The inhibition kinetics analyses and ethidium bromide displacement assays indicated that the carbazole derivatives are competitive inhibitors and not intercalators. An HeLa4.5/LTR-nEGFP cell line was employed to evaluate in vitro virus replication inhibition of the carbazole derivatives, and IC50 levels ranged from 0.48–1.52 μM. Thus, it is possible that carbazole derivatives, which possess structures different from previously-reported IN inhibitors, may become novel lead compounds in the development of IN inhibitors.
3
Asai, Takashi, Tsutomu Takeuchi, Jeff Diffenderfer, and L. David Sibley. "Identification of Small-Molecule Inhibitors of Nucleoside Triphosphate Hydrolase in Toxoplasma gondii." Antimicrobial Agents and Chemotherapy 46, no. 8 (August 2002): 2393–99. http://dx.doi.org/10.1128/aac.46.8.2393-2399.2002.
Abstract:
ABSTRACT Approximately 150,000 small-molecule compounds were tested by a robotic screening assay for their ability to inhibit nucleoside triphosphate hydrolase (NTPase), a novel enzyme of the tachyzoite form of Toxoplasma gondii. Five unrelated species of compounds were found to inhibit the activities of both NTPase isoforms (NTPase isoform I [NTPase-I] and NTPase-II). The 50% inhibitory concentrations (IC50s) ranged from 0.1 to 20 μM, and in general, the IC50s were similar for both NTPase isoforms. However, the activity of NTPase-I was 20 times more sensitive than the activity of NTPase-II to one of the inhibitors: 9-hydroxy-10-(pentachlorophenoxy)stearic acid. The five compounds identified also prevented tachyzoite replication in vitro, with IC50s ranging from ∼7 to ≥50 μM. The most effective of these initial compounds, 2-phenylthio-indole, was used to identify six additional, structurally related compounds, which were tested for their inhibitory effects on enzyme activities and tachyzoite replication. Surprisingly, these compounds were competitive inhibitors of NTPase-I but noncompetitive inhibitors of NTPase-II. Modifications to the indole and phenol rings resulted in alterations of activity, thus providing insight into the structural features that are important for inhibition of T. gondii NTPases.
4
Patkar, Chinmay G., Martha Larsen, Michael Owston, Janet L. Smith, and Richard J. Kuhn. "Identification of Inhibitors of Yellow Fever Virus Replication Using a Replicon-Based High-Throughput Assay." Antimicrobial Agents and Chemotherapy 53, no. 10 (August 3, 2009): 4103–14. http://dx.doi.org/10.1128/aac.00074-09.
Abstract:
ABSTRACT Flaviviruses cause severe disease in humans and are a public health priority worldwide. However, no effective therapies or drugs are commercially available yet. Several flavivirus replicon-based assays amenable to high-throughput screening of inhibitors have been reported recently. We developed and performed a replicon-based high-throughput assay for screening small-molecule inhibitors of yellow fever virus (YFV) replication. This assay utilized packaged pseudoinfectious particles containing a YFV replicon that expresses Renilla luciferase in a replication-dependent manner. Several small-molecule compounds with inhibitory activity at micromolar concentrations were identified in the high-throughput screen. These compounds were subsequently tested for their inhibitory activities against YFV replication and propagation in low-throughput assays. Furthermore, YFV mutants that escaped inhibition by two of the compounds were isolated, and in both cases, the mutations were mapped to the NS4B coding region, suggesting a novel inhibitory target for these compounds. This study opens up new avenues for pursuing the nonenzymatic nonstructural proteins as targets for antivirals against YFV and other flaviviruses.
5
Han, Chun, Jiahong Ren, Feng Su, Xiaoqin Hu, Mengyao Li, Zhijun Wang, and Lintao Wu. "Hybrids of Quinoline and Anilinopyrimidine: Novel EGFRT790M Inhibitors with Antiproliferative Activity against Non-Small Cell Lung Cancer Cell Lines." Anti-Cancer Agents in Medicinal Chemistry 20, no. 6 (June 14, 2020): 724–33. http://dx.doi.org/10.2174/1871520620666200302113206.
Abstract:
Background: The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation confers resistance to existing irreversible EGFRT790M inhibitors. Objective: Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine, and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell lines. Methods: The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking studies were also performed on the representative typical EGFRT790M inhibitor. Results: Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565μM) showed stronger inhibition than gefitinib (IC50 = 8.830 ± 0.495μM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed EGFRL858R/T790M (IC50 = 0.515 ± 0.011μM) relative to EGFRWT (IC50 = 0.913 ± 0.068μM). Furthermore, molecular docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen bonds and other non-bonded interactions. Conclusion: Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies.
6
Abramić, Marija, and Dejan Agić. "Survey of Dipeptidyl Peptidase III Inhibitors: From Small Molecules of Microbial or Synthetic Origin to Aprotinin." Molecules 27, no. 9 (May 7, 2022): 3006. http://dx.doi.org/10.3390/molecules27093006.
Abstract:
Dipeptidyl peptidase III (DPP III) was originally thought to be a housekeeping enzyme that contributes to intracellular peptide catabolism. More specific roles for this cytosolic metallopeptidase, in the renin-angiotensin system and oxidative stress regulation, were confirmed, or recognized, only recently. To prove indicated (patho)physiological functions of DPP III in cancer progression, cataract formation and endogenous pain modulation, or to reveal new ones, selective and potent inhibitors are needed. This review encompasses natural and synthetic compounds with experimentally proven inhibitory activity toward mammalian DPP III. Except for the polypeptide aprotinin, all others are small molecules and include flavonoids, coumarin and benzimidazole derivatives. Presented are current strategies for the discovery or development of DPP III inhibitors, and mechanisms of inhibitory actions. The most potent inhibitors yet reported (propioxatin A and B, Tyr-Phe- and Phe-Phe-NHOH, and JMV-390) are active in low nanomolar range and contain hydroxamic acid moiety. High inhibitory potential possesses oligopeptides from the hemorphin group, valorphin and tynorphin, which are poor substrates of DPP III. The crystal structure of human DPP III-tynorphin complex enabled the design of the transition-state peptidomimetics inhibitors, effective in low micromolar concentrations. A new direction in the field is the development of fluorescent inhibitor for monitoring DPP III activity.
7
Noueiry, Amine O., Paul D. Olivo, Urszula Slomczynska, Yi Zhou, Ben Buscher, Brian Geiss, Michael Engle, et al. "Identification of Novel Small-Molecule Inhibitors of West Nile Virus Infection." Journal of Virology 81, no. 21 (August 22, 2007): 11992–2004. http://dx.doi.org/10.1128/jvi.01358-07.
Abstract:
ABSTRACT West Nile virus (WNV) has spread throughout the United States and Canada and now annually causes a clinical spectrum of human disease ranging from a self-limiting acute febrile illness to acute flaccid paralysis and lethal encephalitis. No therapy or vaccine is currently approved for use in humans. Using high-throughput screening assays that included a luciferase expressing WNV subgenomic replicon and an NS1 capture enzyme-linked immunosorbent assay, we evaluated a chemical library of over 80,000 compounds for their capacity to inhibit WNV replication. We identified 10 compounds with strong inhibitory activity against genetically diverse WNV and Kunjin virus isolates. Many of the inhibitory compounds belonged to a chemical family of secondary sulfonamides and have not been described previously to inhibit WNV or other related or unrelated viruses. Several of these compounds inhibited WNV infection in the submicromolar range, had selectivity indices of greater than 10, and inhibited replication of other flaviviruses, including dengue and yellow fever viruses. One of the most promising compounds, AP30451, specifically blocked translation of a yellow fever virus replicon but not a Sindbis virus replicon or an internal ribosome entry site containing mRNA. Overall, these compounds comprise a novel class of promising inhibitors for therapy against WNV and other flavivirus infections in humans.
8
Lefas, Georgia, and George Chaconas. "High-Throughput Screening Identifies Three Inhibitor Classes of the Telomere Resolvase from the Lyme Disease Spirochete." Antimicrobial Agents and Chemotherapy 53, no. 10 (July 13, 2009): 4441–49. http://dx.doi.org/10.1128/aac.00529-09.
Abstract:
ABSTRACT Lyme disease, the most common vector-borne zoonosis in North America, is caused by the spirochetal pathogen Borrelia burgdorferi. The telomere resolvase encoded by this organism (ResT) promotes the formation of covalently closed hairpin ends on the linear DNA molecules of B. burgdorferi through a two-step transesterification. ResT is essential for survival and is therefore an attractive target for the development of highly specific antiborrelial drugs. To identify ResT inhibitors, a novel fluorescence-based high-throughput assay was developed and used to screen a library of 27,520 small-molecule drug-like compounds. Six confirmed inhibitors of ResT, with 50% inhibitory concentrations between 2 and 10 μM, were identified. The inhibitors were characterized further and were grouped into three distinct classes based on their inhibitory features. The high-throughput screening assay developed in this paper, along with the six inhibitory compounds identified, provides a starting point for the future development of novel antiborrelial drugs as well as small-molecule inhibitors that will be helpful for the further dissection of the reaction mechanism.
9
Ercan-Fang, Nacide, Miriam R. Taylor, Judith L. Treadway, Carolyn B. Levy, Paul E. Genereux, E. Michael Gibbs, Virginia L. Rath, Younggil Kwon, Mary C. Gannon, and Frank Q. Nuttall. "Endogenous effectors of human liver glycogen phosphorylase modulate effects of indole-site inhibitors." American Journal of Physiology-Endocrinology and Metabolism 289, no. 3 (September 2005): E366—E372. http://dx.doi.org/10.1152/ajpendo.00264.2004.
Abstract:
Phosphorylase is regulated by a number of small-molecular-weight effectors that bind to three sites on the enzyme. Recently, a fourth site referred to as the indole-inhibitor site has been identified. Synthetic compounds bind to the site and inhibit activity. However, the effects of these compounds in the presence of other endogenous effectors are unknown. We have determined the effects of four indole derivative glycogen phosphorylase inhibitors (GPI) on recombinant human liver glycogen phosphorylase a activity. The GPIs tested were all potent inhibitors. However, the endogenous inhibitors (glucose, ADP, ATP, fructose 1-phosphate, glucose 6-phosphate, UDP-glucose) and the activator (AMP) markedly reduced the inhibitory effect of GPIs. Consistent with these in vitro findings, the IC50 for the inhibition of glycogenolysis in cells and the liver drug concentration associated with glucose-lowering activity in diabetic ob/ ob mice in vivo were also significantly higher than those determined in in vitro enzyme assays. The inhibitory effect of indole-site effectors is modulated by endogenous small-molecular-weight effectors of phosphorylase a activity. However, at higher concentrations (10–30 μM), the GPI effect was dominant and resulted in inhibition of phosphorylase a activity irrespective of the presence or absence of the other modulators of the enzyme.
10
Yoo, Jihye, Darong Kim, Jiyoung Park, Young-Kook Kim, Hea-Young Park Choo, and Hyun Ae Woo. "Novel Small Molecule Inhibitors Targeting the IL-6/STAT3 Pathway or IL-1β." Molecules 27, no. 9 (April 22, 2022): 2696. http://dx.doi.org/10.3390/molecules27092696.
Abstract:
Development of small molecules that inhibit inflammatory cytokines is a desirable strategy for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Following up a previous study, we synthesized 10 novel compounds with a 2,5-diaminobenzoxazole moiety and evaluated their biological activities. Among them, compound 3e showed potent inhibitory activity on Interleukin 6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling inhibition (71.5%), and 3a showed excellent inhibitory activity on Interleukin 1 (IL-1β) (92.1%). To test in vivo anti-inflammatory activity, compounds 3a and 3e were administered by intraperitoneal (IP) injection after subcutaneous (SC) injection of zymosan A into the right footpad of mice. Inflammation on the footpad was reduced after administration of compounds 3a and 3e. Especially, compound 3a showed a significant ameliorative effect on zymosan-induced inflammation. From the in vivo and in vitro test results, we confirmed that our synthesized compounds are effective on the RA animal model through inhibition of the IL-6/STAT3 signaling pathway. Since drugs developed with small molecule inhibitors have several advantages over biological drugs, further study on these compounds is needed for the development of potent SMI drugs on RA.
11
Ramesh, Priyanka, and Shanthi Veerappapillai. "Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy." Molecules 27, no. 5 (February 28, 2022): 1590. http://dx.doi.org/10.3390/molecules27051590.
Abstract:
Rearranged during transfection (RET) is an oncogenic driver receptor that is overexpressed in several cancer types, including non-small cell lung cancer. To date, only multiple kinase inhibitors are widely used to treat RET-positive cancer patients. These inhibitors exhibit high toxicity, less efficacy, and specificity against RET. The development of drug-resistant mutations in RET protein further deteriorates this situation. Hence, in the present study, we aimed to design novel drug-like compounds using a fragment-based drug designing strategy to overcome these issues. About 18 known inhibitors from diverse chemical classes were fragmented and bred to form novel compounds against RET proteins. The inhibitory activity of the resultant 115 hybrid molecules was evaluated using molecular docking and RF-Score analysis. The binding free energy and chemical reactivity of the compounds were computed using MM-GBSA and density functional theory analysis, respectively. The results from our study revealed that the developed hybrid molecules except for LF21 and LF27 showed higher reactivity and stability than Pralsetinib. Ultimately, the process resulted in three hybrid molecules namely LF1, LF2, and LF88 having potent inhibitory activity against RET proteins. The scrutinized molecules were then subjected to molecular dynamics simulation for 200 ns and MM-PBSA analysis to eliminate a false positive design. The results from our analysis hypothesized that the designed compounds exhibited significant inhibitory activity against multiple RET variants. Thus, these could be considered as potential leads for further experimental studies.
12
Gong, Mengdie, Mingyan Tu, Hongxia Sun, Lu Li, Lili Zhu, Honglin Li, Zhenjiang Zhao, and Shiliang Li. "Design, Synthesis, and Structure–Activity Relationship Study of Potent MAPK11 Inhibitors." Molecules 27, no. 1 (December 29, 2021): 203. http://dx.doi.org/10.3390/molecules27010203.
Abstract:
Huntington’s disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC50 values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure–activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD.
13
Tian, Tao, Guo-Ying Chen, Hao Zhang, and Feng-Qing Yang. "Personal Glucose Meter for α-Glucosidase Inhibitor Screening Based on the Hydrolysis of Maltose." Molecules 26, no. 15 (July 30, 2021): 4638. http://dx.doi.org/10.3390/molecules26154638.
Abstract:
As a key enzyme regulating postprandial blood glucose, α-Glucosidase is considered to be an effective target for the treatment of diabetes mellitus. In this study, a simple, rapid, and effective method for enzyme inhibitors screening assay was established based on α-glucosidase catalyzes reactions in a personal glucose meter (PGM). α-glucosidase catalyzes the hydrolysis of maltose to produce glucose, which triggers the reduction of ferricyanide (K3[Fe(CN)6]) to ferrocyanide (K4[Fe(CN)6]) and generates the PGM detectable signals. When the α-glucosidase inhibitor (such as acarbose) is added, the yield of glucose and the readout of PGM decreased accordingly. This method can achieve the direct determination of α-glucosidase activity by the PGM as simple as the blood glucose tests. Under the optimal experimental conditions, the developed method was applied to evaluate the inhibitory activity of thirty-four small-molecule compounds and eighteen medicinal plants extracts on α-glucosidase. The results exhibit that lithospermic acid (52.5 ± 3.0%) and protocatechualdehyde (36.8 ± 2.8%) have higher inhibitory activity than that of positive control acarbose (31.5 ± 2.5%) at the same final concentration of 5.0 mM. Besides, the lemon extract has a good inhibitory effect on α-glucosidase with a percentage of inhibition of 43.3 ± 3.5%. Finally, the binding sites and modes of four active small-molecule compounds to α-glucosidase were investigated by molecular docking analysis. These results indicate that the PGM method is feasible to screening inhibitors from natural products with simple and rapid operations.
14
Flaumenhaft, Robert, Lynn VerPlank, James R. Dilks, Price S. Blair, Albert Mairuhu, Joseph Negri, Jason Burbank, et al. "A Chemical Genetic Analysis of Platelet Activation." Blood 114, no. 22 (November 20, 2009): 4009. http://dx.doi.org/10.1182/blood.v114.22.4009.4009.
Abstract:
Abstract Abstract 4009 Poster Board III-945 Platelets are anucleate cells that are not amenable to traditional forward genetic analysis. In collaboration with the Broad Institute Probe Development Center, we have performed a chemical genetic analysis of platelet activation. Chemical genetics involves exposure of cells to a library of small molecules, identification of compounds that produce a phenotype of interest, and determination of the target of these small molecules. We have used an assay designed both to identify allosteric inhibitors of Protease Activated Receptor-1 (PAR1) and to find inhibitors that selectively target granule release. This assay monitors dense granule secretion mediated by SFLLRN, a PAR1-specific agonist, using a luciferase-based assay system to detect ADP/ATP release. For primary screening, over 300,000 compounds were assayed in duplicate using freshly outdated platelet-rich plasma supplied by several blood banks across the United States. Computational analyses of the primary data demonstrated that approximately 0.2% of compounds showed ≥50% inhibition relative to maximally inhibitory concentrations of the known antiplatelet agent, cilostazol. Secondary screening using 8-point dose response curves were performed on the 629 inhibitory compounds, 742 compounds with inconclusive activity (e.g., ambiguous duplicates in primary screening), and 213 structural analogs of active compounds. These assays identified 367 active compounds with IC50s ≤10 micromolar. Counter screening to exclude luciferase inhibitors demonstrated 137 small molecules that inhibited PAR1-mediated ATP/ADP release without significant inhibition of luciferase. Database mining using PubChem and CAS search engines was performed to assess the selectivity of active compounds. Twenty eight compounds were selected for further testing based on their IC50s in confirmatory assays, lack of activity in unrelated bioassays, and chemical structure. Known platelet inhibitors were excluded. Of the 28 compounds, 16 compounds potently inhibited SFLLRN-induced alpha-granule release from washed platelets, as monitored by P-selectin expression. IC50s for these compounds ranged from <0.3 to 1 micromolar. None of the selected compounds that failed to inhibit alpha-granule release demonstrated significant inhibition of SFLLRN-induced 14C-serotonin release at 10 micromolar. Ongoing studies are directed at selecting best candidates from among the 16 confirmed inhibitory compounds to develop as biological probes that target either PAR1 activation or distal steps in granule secretion. Disclosures: No relevant conflicts of interest to declare.
15
Choi, Ryan, Mowei Zhou, Roger Shek, Jesse W. Wilson, Logan Tillery, Justin K. Craig, Indraneel A. Salukhe, et al. "High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV-2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity." PLOS ONE 16, no. 4 (April 22, 2021): e0250019. http://dx.doi.org/10.1371/journal.pone.0250019.
Abstract:
SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1–20 μM range in vitro. Furthermore, Exebryl-1, a ß-amyloid anti-aggregation molecule for Alzheimer’s therapy, was shown to have antiviral activity between 10 to 66 μM, in Vero 76, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.
16
Ruseva, Nina, Hristina Sbirkova-Dimitrova, Mariyana Atanasova, Ana Marković, Žaklina Šmelcerović, Andrija Šmelcerović, Adriana Bakalova, and Emiliya Cherneva. "Synthesis and DNase I Inhibitory Properties of New Squaramides." Molecules 28, no. 2 (January 5, 2023): 538. http://dx.doi.org/10.3390/molecules28020538.
Abstract:
Three new monosquaramides (3a–c) were synthesized, characterized by IR, NMR and X-ray, and evaluated for inhibitory activity against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. The target compounds inhibited DNase I with IC50 values below 100 μM, being at the same time more potent DNase I inhibitors than crystal violet, used as a positive control. 3-Ethoxy-4-((1-(pyridin-3-yl)propan-2-yl)amino)cyclobut-3-ene-1,2-dione (3c) stood out as the most potent compound, exhibiting a slightly better IC50 value (48.04 ± 7.98 μM) compared to the other two compounds. In order to analyze potential binding sites for the studied compounds with DNase I, a molecular docking study was performed. Compounds 3a–c are among the most potent small organic DNase I inhibitors tested to date.
17
Huang, Yuting, Zhaoxing Li, Yuan Ma, Qianqian Wu, Jianping Kong, Lijuan Zhao, Shunxiang Li, and Juan Li. "Screening for Active Compounds of Acorus calamus against SARS-CoV-2 Viral Protease and Mechanism Prediction." Pharmaceuticals 17, no. 3 (March 1, 2024): 325. http://dx.doi.org/10.3390/ph17030325.
Abstract:
COVID-19, caused by SARS-CoV-2, has emerged as the most destructive emerging infectious disease of the 21st century. Vaccination is an effective method to combat viral diseases. However, due to the constant mutation of the virus, new variants may weaken the efficacy of vaccines. In the current field of new coronavirus research, viral protease inhibitors have emerged as a highly regarded therapeutic strategy. Nevertheless, existing viral protease inhibitors do not fully meet the therapeutic needs. Therefore, this paper turned to traditional Chinese medicine to explore new active compounds. This study focused on 24 isolated compounds from Acorus calamus L. and identified 8 active components that exhibited significant inhibitory effects on SARS-CoV-2 PLpro. Among these, the compound 1R,5R,7S-guaiane-4R,10R-diol-6-one demonstrated the best inhibitory activity with IC50 values of 0.386 ± 0.118 μM. Additionally, menecubebane B and neo-acorane A exhibited inhibitory activity against both Mpro and PLpro proteases, indicating their potential as dual-target inhibitors. The molecular docking results confirmed the stable conformations of these compounds with the key targets and their good activity. ADMET and Lipinski’s rule analyses revealed that all the small molecule ligands possessed excellent oral absorption properties. This study provides an experimental foundation for the discovery of promising antiviral lead compounds.
18
Sato, Yoshiaki, Ikuo Kashiwakura, Masaru Yamaguchi, Hironori Yoshino, Takeshi Tanaka, Ken Ikeda, Zhengmao Ye, Hirotsugu Komatsu, Takao Matsuzaki, and Masato Hosoda. "Discovery of a Novel Small-molecule Interleukin-6 Inhibitor Through Virtual Screening Using Artificial Intelligence." Medicinal Chemistry 18, no. 6 (July 2022): 694–700. http://dx.doi.org/10.2174/1573406418666211116144243.
Abstract:
Background: Interleukin-6 (IL-6) is a multifunctional cytokine involved in various cell functions and diseases. Thus far, several IL-6 inhibitors, such as humanized monoclonal antibody have been used to block excessive IL-6 signaling causing autoimmune and inflammatory diseases. However, anti-IL-6 and anti-IL-6 receptor monoclonal antibodies have some clinical disadvantages, such as a high cost, unfavorable injection route, and tendency to mask infectious diseases. While a small-molecule IL-6 inhibitor would help mitigate these issues, none are currently available. Objective: The present study evaluated the biological activities of identified compounds on IL-6 stimulus. Methods: We virtually screened potential IL-6 binders from a compound library using INTerprotein’s Engine for New Drug Design (INTENDD®) followed by the identification of more potent IL-6 binders with artificial intelligence (AI)-guided INTENDD®. The biological activities of the identified compounds were assessed with the IL-6-dependent cell line 7TD1. Results: The compounds showed the suppression of IL-6-dependent cell growth in a dose-dependent manner. Furthermore, the identified compound inhibited expression of IL-6-induced phosphorylation of signal transducer and activator of transcription 3 in a dose-dependent manner. Conclusion: Our screening compound demonstrated an inhibitory effect on IL-6 stimulus. These findings may serve as a basis for the further development of small-molecule IL-6 inhibitors.
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Paiboonrungruang, chorlada. "Abstract 6237: Small molecule screen identifies pyrimethamine as an inhibitor of NRF2-driven esophageal hyperplasia." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6237. http://dx.doi.org/10.1158/1538-7445.am2023-6237.
Abstract:
Abstract Objective: NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2high ESCC. Design: We performed high-throughput screening of two compound libraries from which hit compounds were further validated in human ESCC cells and a genetically modified mouse model. Mechanism of action of one compound was explored by biochemical assays. Results: Using high-throughput screening of two small molecule compound libraries, we identified 11 hit compounds as potential NRF2 inhibitors with minimal cytotoxicity at specified concentrations. We then validated two of these compounds, pyrimethamine and mitoxantrone, by demonstrating their dose- and time-dependent inhibitory effects on the expression of NRF2 and its target genes in two NRF2Mut human ESCC cells (KYSE70 and KYSE180). RNAseq and qPCR confirmed the suppression of global NRF2 signaling by these two compounds. Mechanistically, pyrimethamine reduced NRF2 half-life by promoting NRF2 ubiquitination and degradation in KYSE70 and KYSE180 cells. Expression of an Nrf2E79Q allele in mouse esophageal epithelium (Sox2CreER;LSL-Nrf2E79Q/+) resulted in an NRF2high phenotype, which included squamous hyperplasia, hyperkeratinization, and hyperactive glycolysis. Treatment with pyrimethamine (30mg/kg/day, p.o.) suppressed the NRF2high esophageal phenotype with no observed toxicity. Conclusion: We have identified and validated pyrimethamine as an NRF2 inhibitor that may be rapidly tested in the clinic as a radiation and chemotherapy sensitizer for NRF2high ESCC. Citation Format: chorlada Paiboonrungruang. Small molecule screen identifies pyrimethamine as an inhibitor of NRF2-driven esophageal hyperplasia [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 6237.
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Jiang, Suping, Sean T. Prigge, Lan Wei, Yu-e. Gao, Thomas H. Hudson, Lucia Gerena, John B. Dame, and Dennis E. Kyle. "New Class of Small Nonpeptidyl Compounds BlocksPlasmodium falciparum Development In Vitro by Inhibiting Plasmepsins." Antimicrobial Agents and Chemotherapy 45, no. 9 (September 1, 2001): 2577–84. http://dx.doi.org/10.1128/aac.45.9.2577-2584.2001.
Abstract:
ABSTRACT Malarial parasites rely on aspartic proteases called plasmepsins to digest hemoglobin during the intraerythrocytic stage. Plasmepsins fromPlasmodium falciparum and Plasmodium vivax have been cloned and expressed for a variety of structural and enzymatic studies. Recombinant plasmepsins possess kinetic similarity to the native enzymes, indicating their suitability for target-based antimalarial drug development. We developed an automated assay of P. falciparum plasmepsin II andP. vivax plasmepsin to quickly screen compounds in the Walter Reed chemical database. A low-molecular-mass (346 Da) diphenylurea derivative (WR268961) was found to inhibit plasmepsins with a K i of 1 to 6 μM. This compound appears to be selective for plasmepsin, since it is a poor inhibitor of the human aspartic protease cathepsin D (K i greater than 280 μM). WR268961 inhibited the growth of P. falciparum strains W2 and D6, with 50% inhibitory concentrations ranging from 0.03 to 0.16 μg/ml, but was much less toxic to mammalian cells. The Walter Reed chemical database contains over 1,500 compounds with a diphenylurea core structure, 9 of which inhibit the plasmepsins, withK i values ranging from 0.05 to 0.68 μM. These nine compounds show specificity for the plasmepsins over human cathepsin D, but they are poor inhibitors of P. falciparum growth in vitro. Computational docking experiments indicate how diphenylurea compounds bind to the plasmepsin active site and inhibit the enzyme.
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Moi, Davide, Alessandro Deplano, Andrea Angeli, Gianfranco Balboni, Claudiu T. Supuran, and Valentina Onnis. "Synthesis of Sulfonamides Incorporating Piperidinyl-Hydrazidoureido and Piperidinyl-Hydrazidothioureido Moieties and Their Carbonic Anhydrase I, II, IX and XII Inhibitory Activity." Molecules 27, no. 17 (August 23, 2022): 5370. http://dx.doi.org/10.3390/molecules27175370.
Abstract:
Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms.
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Al-Sanea, Mohammad M. "Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold." PeerJ 8 (March 13, 2020): e8649. http://dx.doi.org/10.7717/peerj.8649.
Abstract:
Background CDK8/CycC complex has kinase activity towards the carboxyterminal domain of RNA polymerase II, and contributes to the regulation of transcription via association with the mediator complex. Different human malignancies, mainly colorectal and gastric cancers, were produced as a result of overexpression of CDK8/CycC in the mediator complex. Therefore, CDK8/CycC complex represents as a cancer oncogene and it has become a potential target for developing CDK8/CycC modulators. Methods A series of nine 4-phenylaminoquinoline scaffold-based compounds 5a-i was synthesized, and biologically evaluated as potential CDK8/CycC complex inhibitors. Results The scaffold substituent effects on the intrinsic inhibitory activity toward CDK8/CycC complex are addressed trying to present a novel outlook of CDK8/CycC Complex inhibitors with 4-phenylaminoquinoline scaffold in cancer therapy. The secondary benzenesulfonamide analogues proved to be the most potent compounds in suppressing CDK8/CycC enzyme, whereas, their primary benzenesulfonamide analogues showed inferior activity. Moreover, the benzene reversed sulfonamide analogues were totally inactive. Discussion The titled scaffold showed promising inhibitory activity data and there is a crucial role of un/substituted sulfonamido group for CDK8/CycC complex inhibitory activity. Compound 5d showed submicromolar potency against CDK8/CycC (IC50 = 0.639 µM) and it can be used for further investigations and to design another larger library of phenylaminoquinoline scaffold-based analogues in order to establish detailed SARs.
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Gao, Yinghong, Stephen P. Davies, Martin Augustin, Anna Woodward, Umesh A. Patel, Robert Kovelman, and Kevin J. Harvey. "A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery." Biochemical Journal 451, no. 2 (March 28, 2013): 313–28. http://dx.doi.org/10.1042/bj20121418.
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Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.
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Cruz-Migoni, Abimael, Peter Canning, Camilo E. Quevedo, Carole J. R. Bataille, Nicolas Bery, Ami Miller, Angela J. Russell, Simon E. V. Phillips, Stephen B. Carr, and Terence H. Rabbitts. "Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds." Proceedings of the National Academy of Sciences 116, no. 7 (January 25, 2019): 2545–50. http://dx.doi.org/10.1073/pnas.1811360116.
Abstract:
The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein–protein interactions. We have refined crystallization conditions for KRAS169Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein–protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein–protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein–protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules.
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Ramshini, Hassan, Reza Tayebee, Alessandra Bigi, Francesco Bemporad, Cristina Cecchi, and Fabrizio Chiti. "Identification of Novel 1,3,5-Triphenylbenzene Derivative Compounds as Inhibitors of Hen Lysozyme Amyloid Fibril Formation." International Journal of Molecular Sciences 20, no. 22 (November 7, 2019): 5558. http://dx.doi.org/10.3390/ijms20225558.
Abstract:
Deposition of soluble proteins as insoluble amyloid fibrils is associated with a number of pathological states. There is a growing interest in the identification of small molecules that can prevent proteins from undergoing amyloid fibril formation. In the present study, a series of small aromatic compounds with different substitutions of 1,3,5-triphenylbenzene have been synthesized and their possible effects on amyloid fibril formation by hen egg white lysozyme (HEWL), a model protein for amyloid formation, and of their resulting toxicity were examined. The inhibitory effect of the compounds against HEWL amyloid formation was analyzed using thioflavin T and Congo red binding assays, atomic force microscopy, Fourier-transform infrared spectroscopy, and cytotoxicity assays, such as the 3-(4,5-Dimethylthiazol)-2,5-Diphenyltetrazolium Bromide (MTT) reduction assay and caspase-3 activity measurements. We found that all compounds in our screen were efficient inhibitors of HEWL fibril formation and their associated toxicity. We showed that electron-withdrawing substituents such as –F and –NO2 potentiated the inhibitory potential of 1,3,5-triphenylbenzene, whereas electron-donating groups such as –OH, –OCH3, and –CH3 lowered it. These results may ultimately find applications in the development of potential inhibitors against amyloid fibril formation and its biologically adverse effects.
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Minhas, Richa, and Yogita Bansal. "iNOS inhibitors: Benzimidazole-coumarin derivatives to combat inflammation." European Journal of Chemistry 13, no. 3 (September 30, 2022): 307–18. http://dx.doi.org/10.5155/eurjchem.13.3.307-318.2282.
Abstract:
Inducible nitric oxide synthase (iNOS) plays an important role in the inflammatory processes via accelerating the production of nitric oxide (NO). The efforts to develop small molecules as selective inhibitors of iNOS are being reported across the globe. The current study explores varied benzimidazole-coumarin derivatives as anti-iNOS agents. Literature survey suggests 2-aminobenzimidazole, coumarin nucleus, and 4-atom linker as important structural components for iNOS inhibition. Target compounds were designed and synthesized by coupling 2-aminobenzimidazole with (un)substituted coumarin through different linkers. These were docked in iNOS (1QW4) and nNOS (1QW6) targets to ascertain their iNOS selectivity, and evaluated for NO and iNOS inhibitory activities in vitro. The most active inhibitors were subsequently evaluated for acute toxicity and anti-inflammatory activity using carrageenan-induced rat paw edema model in vivo. All compounds possessed moderate to good NO and iNOS inhibitory activities. Compounds 14a, 14b, 14d, and 14e were the most potent inhibitors in vitro. These were found to significantly reduce the inflammation. Compounds 14d and 14e have been identified as the most potent iNOS inhibitors to combat inflammation. These derivatives may serve as potential compounds as such against iNOS, or as leads for the development of novel anti-iNOS agents.
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Chattopadhyay, Shrikanta, Alison L. Stewart, Siddhartha Mukherjee, Cherrie Huang, Kimberly A. Hartwell, Peter G. Miller, Leigh Carmody, et al. "Niche-Based Screening Identifies Novel Small Molecules That Overcome Stromal Effects in Multiple Myeloma." Blood 120, no. 21 (November 16, 2012): 571. http://dx.doi.org/10.1182/blood.v120.21.571.571.
Abstract:
Abstract Abstract 571 Despite advances in the treatment of multiple myeloma (MM), this disease remains incurable and novel therapeutic strategies are urgently needed. Ideal strategies would overcome resistance factors from the bone-marrow microenvironment (niche) since a variety of inhibitors are rendered less effective by bone-marrow stromal cells (BMSCs) of the MM niche (McMillin et al., Nat Med. 2010 Apr;16(4):483–9). Drug discovery often entails a target-based approach but identifying targets in MM is challenging because of its complex genome and multiple niche interactions. We used a chemical biology approach in which small-molecule inhibitors of MM cells, grown within their niche, are first identified and then used to discover targets within MM or its niche. These compounds also serve as leads for future drug discovery. To model myeloma/niche interactions, we chose an MM cell line MOLP5 that has an obligate dependence on BMSCs to maintain viability. Small-molecule inhibitors were identified by screening ∼25,000 structurally diverse small molecules on GFP-labeled MOLP5 cells co-cultured with primary BMSCs derived from hip replacement samples. MOLP5 growth inhibition was measured by quantifying GFP(+) cells with automated high-throughput microscopy. About 800 hits were counter-screened on BMSCs alone to exclude non-specifically toxic compounds. The remaining 182 MOLP5-selective inhibitors were then tested on 2 other GFP-labeled MM cell-lines, MM1S and INA6, in the presence or absence of BMSCs to exclude compounds that are less effective in the presence of BMSCs. The 64 compounds that overcome BMSC resistance were tested on CD34+ human hematopoietic progenitors to prioritize compounds with selectivity between MM and normal blood cells. The 8 compounds that met these criteria fell into 3 categories: 1) compounds with equal activity in the presence or absence of BMSCs (overcome stromal resistance); 2) compounds with selectivity for BMSC-dependent MOLP5 cells (block stromal viability factors); and 3) compounds with increased activity in the presence of BMSCs (enhance stromal inhibitory factors). Because most efficacious clinical compounds like bortezomib act like compounds in category 1, compound BRD9876 was chosen from this category for mechanistic studies. Gene-expression profiling of BRD9876-treated MM1S cells suggested possible links to mitotic arrest and cell cycle analyses revealed a rapid accumulation of cells in the G2/M phase. Treated cells were stained for the mitotic spindle protein α-tubulin and found to exhibit an aberrant mono-astral mitotic phenotype, reminiscent of the kinesin-5 (Eg5; KIF11) inhibitor monastrol. This was encouraging because a kinesin-5 inhibitor ARRY-520 has shown promising durable responses in multiple myeloma (Shah et al, ASH Annual Meeting 2011; Abstract 1860). To determine if BRD9876 was a kinesin-5 inhibitor, a BRD9876-resistant sub-line of MM1S was developed and the kinesin-5 gene sequenced. BRD9876-resistant cells have a novel kinesin-5 mutation (Y104C) at a site that is distant from the monastrol-binding pocket. Most kinesin-5 inhibitors in clinical development bind the monastrol pocket, and the BRD9876-resistant cells were not cross-resistant to one such inhibitor, ispinesib, suggesting a distinct mode of kinesin-5 inhibition by BRD9876. To identify biomarkers of sensitivity to BRD9876, quantitative dose/response measurements in 98 genetically characterized cell lines (Schreiber & co-workers, submitted) comprising a subset of the Cancer Cell Line Encyclopedia (CCLE) were analyzed. Unbiased analyses correlating genetic features with sensitivity revealed that mutations in the mitotic regulator WEE1 were associated with sensitivity to BRD9876. Validation studies comparing WEE1 mutant to wild-type cell lines confirmed enhanced sensitivity of mutant cells to both BRD9876 and ispinesib suggesting that WEE1 mutations could be a useful biomarker for different kinesin-5 inhibitors. In contrast, co-treatment of WEE1 WT cells with sub-toxic concentrations of the WEE1 inhibitor MK1775 led to marked enhancement of BRD9876 activity but had little effect on ispinesib activity, suggesting a unique synergistic relationship between WEE1 inhibitors and BRD9876. In summary, niche-based screening in multiple myeloma has revealed a novel therapeutic candidate and can complement other drug-discovery approaches against this disease. Disclosures: Ebert: Celgene: Consultancy; Genoptix: Consultancy. Raje:Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding.
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Adachi, Ryutaro, Tsuyoshi Ishii, Shinichi Matsumoto, Takuya Satou, Junichi Sakamoto, and Tomohiro Kawamoto. "Discovery of Human Intestinal MGAT Inhibitors Using High-Throughput Mass Spectrometry." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 4 (October 8, 2016): 360–65. http://dx.doi.org/10.1177/1087057116673181.
Abstract:
Monoacylglycerol acyltransferase (MGAT) activity catalyzes the synthesis of diacylglycerol (DAG) from fatty acyl-CoA and monoacylglycerol as substrates. It is important for the resynthesis of triacylglycerol (TAG) in the intestine. In the present study, we developed a MGAT enzymatic assay of human intestinal microsomes using a high-throughput mass spectrometry (MS)–based detection system. After screening with small-molecular-weight libraries for compounds exhibiting inhibitions against DAG and the consequent TAG syntheses, we identified multiple compounds that specifically inhibit intestinal MGAT activity. The inhibitory activities of these compounds were correlated to those determined using a recombinant human MGAT2 enzyme. An aryl-sulfonamide compound T1 showed potent inhibitory activity toward human intestinal MGAT and recombinant human MGAT2, with selectivity over MGAT3. This high-throughput MS-based assay provides a novel platform for the discovery of DAG or TAG synthesis inhibitors. The identified aryl-sulfonamide compound T1 is a promising starting compound for optimization studies of inhibitors with selectivity toward MGAT2.
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Mavridis, Evangelos, Eleftherios Bermperoglou, Eleni Pontiki, and Dimitra Hadjipavlou-Litina. "5-(4H)-Oxazolones and Their Benzamides as Potential Bioactive Small Molecules." Molecules 25, no. 14 (July 11, 2020): 3173. http://dx.doi.org/10.3390/molecules25143173.
Abstract:
The five membered heterocyclic oxazole group plays an important role in drug discovery. Oxazolones present a wide range of biological activities. In this article the synthesis of 4-substituted-2-phenyloxazol-5(4H)-ones from the appropriate substituted aldehydes via an Erlenmeyer–Plochl reaction is reported. Subsequently, the corresponding benzamides were produced via a nucleophilic attack of a secondary amine on the oxazolone ring applying microwave irradiation. The compounds are obtained in good yields up to 94% and their structures were confirmed using IR, 1H-NMR, 13C-NMR and LC/MS data. The in vitro anti-lipid peroxidation activity and inhibitory activity against lipoxygenase and trypsin induced proteolysis of the novel derivatives were studied. Inhibition of carrageenin-induced paw edema (CPE) and nociception was also determined for compounds 4a and 4c. Oxazolones 2a and 2c strongly inhibit lipid peroxidation, followed by oxazolones 2b and 2d with an average inhibition of 86.5%. The most potent lipoxygenase inhibitor was the bisbenzamide derivative 4c, with IC50 41 μM. The benzamides 3c, 4a–4e and 5c were strong inhibitors of proteolysis. The replacement of the thienyl moiety by a phenyl group does not favor the protection. Compound 4c inhibited nociception higher than 4a. The replacement of thienyl groups by phenyl ring led to reduced biological activity. Docking studies of the most potent LOX inhibitor highlight interactions through allosteric mechanism. All the potent derivatives present good oral bioavailability.
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Trenholme, Katharine, Linda Marek, Sandra Duffy, Gabriele Pradel, Gillian Fisher, Finn K. Hansen, Tina S. Skinner-Adams, et al. "Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules." Antimicrobial Agents and Chemotherapy 58, no. 7 (April 14, 2014): 3666–78. http://dx.doi.org/10.1128/aac.02721-13.
Abstract:
ABSTRACTTherapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein inPlasmodium falciparumgametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed inP. falciparumgametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.
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Zhao, Hongchuan, Pu Sun, Wei Guo, Yi Wang, Ao Zhang, Linghua Meng, and Chunyong Ding. "Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO-1) Inhibitors Based on Ortho-Naphthaquinone-Containing Natural Product." Molecules 24, no. 6 (March 18, 2019): 1059. http://dx.doi.org/10.3390/molecules24061059.
Abstract:
There is great interest in developing small molecules agents capable of reversing tumor immune escape to restore the body’s immune system. As an immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1) is considered a promising target for oncology immunotherapy. Currently, none of IDO-1 inhibitors have been launched for clinical practice yet. Thus, the discovery of new IDO-1 inhibitors is still in great demand. Herein, a series of diverse ortho-naphthaquinone containing natural product derivatives were synthesized as novel IDO-1 inhibitors. Among them, 1-ene-3-ketone-17-hydroxyl derivative 12 exhibited significantly improved enzymatic and cellular inhibitory activity against IDO-1 when compared to initial lead compounds. Besides, the molecular docking study disclosed that the two most potent compounds 11 and 12 have more interactions within the binding pocket of IDO-1 via hydrogen-bonding, which may account for their higher IDO-1 inhibitory activity.
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Furbish, Amelia B., Ahmed S. Alford, Pieter Burger, Yuri K. Peterson, Tracy Murray-Stewart, Robert A. Casero, and Patrick M. Woster. "Identification and Characterization of Novel Small-Molecule SMOX Inhibitors." Medical Sciences 10, no. 3 (August 30, 2022): 47. http://dx.doi.org/10.3390/medsci10030047.
Abstract:
The major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxic, ischemic, and inflammatory states. In addition to the loss of radical scavenging capabilities associated with spermine depletion, the catabolism of spermine by SMOX results in the production of toxic byproducts, including H2O2 and acrolein, a highly toxic aldehyde with the ability to form adducts with DNA and inactivate vital cellular proteins. Despite extensive evidence implicating SMOX as a key enzyme contributing to secondary injury associated with multiple pathologic states, the lack of potent and selective inhibitors has significantly impeded the investigation of SMOX as a therapeutic target. In this study, we used a virtual and physical screening approach to identify and characterize a series of hit compounds with inhibitory activity against SMOX. We now report the discovery of potent and highly selective SMOX inhibitors 6 (IC50 0.54 μM, Ki 1.60 μM) and 7 (IC50 0.23 μM, Ki 0.46 μM), which are the most potent SMOX inhibitors reported to date. We hypothesize that these selective SMOX inhibitors will be useful as chemical probes to further elucidate the impact of polyamine catabolism on mechanisms of cellular injury.
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VENÄLÄINEN, Jarkko I., Risto O. JUVONEN, J. Arturo GARCIA-HORSMAN, Erik A. A. WALLÉN, Johannes A. M. CHRISTIAANS, Elina M. JARHO, Jukka GYNTHER, and Pekka T. MÄNNISTÖ. "Slow-binding inhibitors of prolyl oligopeptidase with different functional groups at the P1 site." Biochemical Journal 382, no. 3 (September 7, 2004): 1003–8. http://dx.doi.org/10.1042/bj20040992.
Abstract:
POP (prolyl oligopeptidase) specifically hydrolyses a number of small proline-containing peptides at the carboxy end of the proline residue and POP inhibitors have been shown to have cognition-enhancing properties. It has been noted that certain functional groups at the P1 site of the inhibitor, which correspond to the substrate residue on the N-terminal side of the bond to be cleaved, increase the inhibitory potency. However, detailed mechanistic and kinetic analysis of the inhibition has not been studied. In the present study, we examined the effect of different functional groups at the P1 site of the parent inhibitor isophthalic acid bis-(L-prolylpyrrolidine) amide on the binding kinetics to POP. Addition of CHO, CN or COCH2OH groups to the P1 site increased the inhibitory potency by two orders of magnitude (Ki=11.8–0.1 nM) and caused a clear slow-binding inhibition. The inhibitor containing a CHO group had the lowest association rate constant, kon=(2.43±0.12)×105 M−1·s−1, whereas the inhibitor with a CN group exhibited the fastest binding, kon=(12.0±0.08)×105 M−1·s−1. In addition, the dissociation rate was found to be crucially dependent on the type of the functional group. Compounds with COCH2OH and CHO groups had much longer half-lives of dissociation (over 5 h) compared with the compound with the CN group (25 min), although the Ki values of the compounds were relatively similar. A possibility to optimize the duration of inhibition by changing the functional group at the P1 site is important when planning therapeutically useful POP inhibitors.
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Kollár, Levente, Martina Gobec, Matic Proj, Lara Smrdel, Damijan Knez, Tímea Imre, Ágnes Gömöry, et al. "Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads." Cells 10, no. 12 (December 6, 2021): 3431. http://dx.doi.org/10.3390/cells10123431.
Abstract:
Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.
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Nordio, Giulia, Francesco Piazzola, Giorgio Cozza, Monica Rossetto, Manuela Cervelli, Anna Minarini, Filippo Basagni, et al. "From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs." Molecules 28, no. 17 (August 29, 2023): 6329. http://dx.doi.org/10.3390/molecules28176329.
Abstract:
Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2–7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.
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Moon, Sungho, Seon Yeon Cho, Minhye Kim, Soojeong Beak, Jinhyuk Kim, Yongchan Kim, Sungil Park, et al. "Abstract B142: Discovery of novel and potent TEAD inhibitors, orally available small molecules with anti-tumor activity in hippo pathway- dysregulated cancers." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): B142. http://dx.doi.org/10.1158/1535-7163.targ-23-b142.
Abstract:
Abstract Hippo pathway plays a critical role in cell apoptosis, proliferation, tissue homeostasis. Dysregulation of Hippo pathway was reported to related to overall aspects of tumorigenesis. The higher expression a YAP/TAZ and TEADs or mutation of core components of hippo pathway, such as NF2, MST1/2 and LATS1/2 were reported in various cancer subtypes including mesothelioma, meningioma, glioblastoma, non-small cell lung cancer. TEAD auto-palmitoylation is required for protein stability and its transcriptional activity. Inhibiting TEAD activity regulation present attractive strategy for therapeutic intervention in the Hippo pathway. There are increasing proof that the inhibitor to central pocket of TEAD can be promising candidate for cancer treatment. We validated and optimized the hits, derived from our in silico screening system. Our lead compounds inhibiting palmitoylation of TEADs are the potent in vitro activities in TEAD reporter assay and hippo pathway-dysregulated mesotheliomas. In addition, these compounds reduced the expression of TEAD target genes. Furthermore, our compounds strongly inhibited tumor growth in NF2 deficient mouse xenograft model without any adverse events. In these models, our compounds showed excellent PK-PD correlation. Using these compounds, we also tested the possibility as therapy for combination drugs with KRAS inhibitor, EGFR inhibitors. In summary, we have potent TEAD inhibitor series, that showed inhibitory activities of tumor growth in NF2 deficient in vivo models, and may have therapeutic potential in diverse solid tumors. Citation Format: Sungho Moon, Seon Yeon Cho, Minhye Kim, Soojeong Beak, Jinhyuk Kim, Yongchan Kim, Sungil Park, Jung-In Kim, Hanseong Kim, In Sang Lee, Kyoung Tai No. Discovery of novel and potent TEAD inhibitors, orally available small molecules with anti-tumor activity in hippo pathway- dysregulated cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B142.
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Rusina, Polina, Erik Gandalipov, Yana Abdusheva, Maria Panova, Alexandra Burdenkova, Vasiliy Chaliy, Maria Brachs, et al. "Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases." Cancers 15, no. 15 (July 25, 2023): 3766. http://dx.doi.org/10.3390/cancers15153766.
Abstract:
The rational design of cyclin-dependent protein kinase (CDK) inhibitors presumes the development of approaches for accurate prediction of selectivity and the activity of small molecular weight anticancer drug candidates. Aiming at attenuation of general toxicity of low selectivity compounds, we herein explored the new chemotype of imidazole-4-N-acetamide substituted derivatives of the pan-CDK inhibitor PHA-793887. Newly synthesized compounds 1–4 containing an aliphatic methyl group or aromatic radicals at the periphery of the scaffold were analyzed for the prediction of relative free energies of binding to CDK1, -2, -5, and -9 using a protocol based on non-equilibrium (NEQ) thermodynamics. This methodology allows for the demonstration of a good correlation between the calculated parameters of interaction of 1–4 with individual targets and the values of inhibitory potencies in in vitro kinase assays. We provide evidence in support of NEQ thermodynamics as a time sparing, precise, and productive approach for generating chemical inhibitors of clinically relevant anticancer targets.
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Francini, Cinzia, Francesca Musumeci, Anna Fallacara, Lorenzo Botta, Alessio Molinari, Roberto Artusi, Laura Mennuni, Adriano Angelucci, and Silvia Schenone. "Optimization of Aminoimidazole Derivatives as Src Family Kinase Inhibitors." Molecules 23, no. 9 (September 17, 2018): 2369. http://dx.doi.org/10.3390/molecules23092369.
Abstract:
Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. We previously reported a small library of 4-aminoimidazole and 2-aminothiazole derivatives active as Src family kinase (SFK) inhibitors. Starting from these results, we decided to perform an optimization study applying a mix and match strategy to identify a more potent generation of 4-aminoimidazoles. Firstly, a computational study has been performed, then compounds showing the best predicted docking scores were synthesized and screened in a cell-free assay for their SFK inhibitory activity. All the new chemical entities showed IC50s in the nanomolar range, with 2–130 fold increased activities compared to the previously reported inhibitors. Finally, the most active compounds have been tested on three cancer cell lines characterized by Src hyperactivation. Compounds 4k and 4l showed an interesting antiproliferative activity on SH-SY5Y neuroblastoma (NB) cell line. In this assay, the compounds resulted more potent than dasatinib, a tyrosine kinase inhibitor approved for the treatment of leukemias and in clinical trials for NB.
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Kulkarni, Amol A., Ayyiliath M. Sajith, Changwen Zhang, Jiukuan Hao, and J. Phillip Bowen. "Small molecule prevents inflammation in microglia by targeting the NLRP3 inflammasome." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 160.15. http://dx.doi.org/10.4049/jimmunol.204.supp.160.15.
Abstract:
Abstract Uncontrolled CNS inflammation forms the pathophysiological basis of numerous disorders, including Alzheimer’s disease (AD). Evidence strongly suggests that the inhibition of the NLRP3 inflammasome is a promising strategy for the treatment of AD. A variety of natural products including curcumin, resveratrol, and isoliquiritigenin have displayed encouraging in vitro NLRP3 inhibitory activity. These natural products, however, are reported to display low chemical and/or enzymatic stability and therefore are not considered as promising leads for drug discovery. Using computer-assisted drug design methods and classical medicinal chemistry approaches, we developed a small library of tertiary sulfonylurea compounds that resembled the 3D-structure of the aforementioned natural products without the moieties responsible for the reported chemical and enzymatic instability. The compounds were synthesized, characterized, and tested for their inflammasome inhibitory activity. Preliminary studies indicated two of our compounds decreased the NLRP3 expression in a dose-dependent manner. These compounds reduced the production of inflammatory markers, such as, IL-1b, TNF-a, and caspase 1. These compounds lower the levels of inducible nitric oxide synthase and NO biosynthesis. MTT assays revealed that the sulfonylurea compounds did not affect N9 cell viability. Using computational chemistry and pharmacophore modeling, our efforts are currently on structural modifications to improve their biological activity and penetration the blood-brain barrier.
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Rampogu, Shailima, Ayoung Baek, Chanin Park, Shraddha Parate, Saravanan Parameswaran, Yohan Park, Baji Shaik, Ju Hyun Kim, Seok Ju Park, and Keun Woo Lee. "Discovery of Small Molecules that Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies." Cells 8, no. 3 (March 21, 2019): 269. http://dx.doi.org/10.3390/cells8030269.
Abstract:
Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed with axitinib and was subsequently validated and employed as a 3D query to retrieve the candidate compounds with the key inhibitory features. The model was escalated to molecular docking studies resulting in seven candidate compounds. The molecular docking studies revealed that the seven compounds displayed a higher dock score than the reference-cocrystallised compound. The GROningen MAchine for Chemical Simulations (GROMACS) package guided molecular dynamics (MD) results determined their binding mode and affirmed stable root mean square deviation. Furthermore, these compounds have preserved their key interactions with the residues Glu885, Glu917, Cys919 and Asp1046. The obtained findings deem that the seven compounds could act as novel anti-angiogenic inhibitors and may further assist as the prototype in designing and developing new inhibitors.
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Gising, Johan, Saman Honarnejad, Maaike Bras, Gemma L. Baillie, Stuart P. McElroy, Philip S. Jones, Angus Morrison, Julia Beveridge, Mathias Hallberg, and Mats Larhed. "The Discovery of New Inhibitors of Insulin-Regulated Aminopeptidase by a High-Throughput Screening of 400,000 Drug-like Compounds." International Journal of Molecular Sciences 25, no. 7 (April 6, 2024): 4084. http://dx.doi.org/10.3390/ijms25074084.
Abstract:
With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.
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Curreli, Francesca, Shahad Ahmed, Sofia M. B. Victor, Aleksandra Drelich, Siva S. Panda, Andrea Altieri, Alexander V. Kurkin, Chien-Te K. Tseng, Christopher D. Hillyer, and Asim K. Debnath. "Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays." Viruses 14, no. 1 (December 31, 2021): 69. http://dx.doi.org/10.3390/v14010069.
Abstract:
We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell–cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.
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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.
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.
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Porubin, Diana. "Inhibition of in Vitro Nitrosation of Nornicotine." Chemistry Journal of Moldova 2, no. 1 (December 2007): 78–82. http://dx.doi.org/10.19261/cjm.2007.02(1).11.
Abstract:
The inhibition of nornicotine nitrosation was studied. The concentration of nornicotine was 100 μM and nitrite 1000 μM. As inhibitors were used following compounds: ascorbic acid (as reference) (800, 1000, and 5000 μM), dihydroxyfumaric acid (1000 μM), (+)catechin (1000 μM), resveratrol (1000 μM), tartaric acid (1000 μM), quercetin (1000 μM), and grape seed extract (50, 100, 150 μg/ml). The best inhibitory effect was obtained for AAs at 5000 μM (90.7%), (+)Ct (95.5 %) and GSE at 150 μg/ml (96.1%). The small inhibitory effect was observed for TA – 22,5%.
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Montanari, Floriane, Anna Cseke, Katrin Wlcek, and Gerhard F. Ecker. "Virtual Screening of DrugBank Reveals Two Drugs as New BCRP Inhibitors." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 1 (July 11, 2016): 86–93. http://dx.doi.org/10.1177/1087057116657513.
Abstract:
The breast cancer resistance protein (BCRP) is an ABC transporter playing a crucial role in the pharmacokinetics of drugs. The early identification of substrates and inhibitors of this efflux transporter can help to prevent or foresee drug-drug interactions. In this work, we built a ligand-based in silico classification model to predict the inhibitory potential of drugs toward BCRP. The model was applied as a virtual screening technique to identify potential inhibitors among the small-molecules subset of DrugBank. Ten compounds were selected and tested for their capacity to inhibit mitoxantrone efflux in BCRP-expressing PLB985 cells. Results identified cisapride (IC50 = 0.4 µM) and roflumilast (IC50 = 0.9 µM) as two new BCRP inhibitors. The in silico strategy proved useful to prefilter potential drug-drug interaction perpetrators among a database of small molecules and can reduce the amount of compounds to test.
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Zhang, Hao, Feng-Qing Yang, and Jian-Li Gao. "A Simple and Portable Personal Glucose Meter Method Combined with Molecular Docking for Screening of Lipase Inhibitors." Evidence-Based Complementary and Alternative Medicine 2022 (September 22, 2022): 1–9. http://dx.doi.org/10.1155/2022/4430050.
Abstract:
With the increase of obesity incidence, the development of antiobesity drugs has aroused extensive interest. In this study, a simple and portable personal glucose meter (PGM) method based on the lipase-mediated reaction combined with molecular docking was developed for the screening of lipase inhibitors. Lipase can catalyse the hydrolysis of 4-acetamidophenyl acetate to form acetaminophen, which can directly trigger the reduction of K3[Fe(CN)6] to K4[Fe(CN)6] in the glucose test strips and generate an electrical signal that can be detected by the PGM. When lipase inhibitors exist, the yield of acetaminophen will be reduced and results in a corresponding decrease of the PGM signal. Therefore, the activity of lipase can be measured by the PGM. After optimization of the experimental conditions, the inhibitory activity of fourteen small-molecule compounds and fifteen natural product extracts on lipase were evaluated by the developed PGM method. The results indicate that tannic acid, (-)-epigallocatechin gallate, (-)-epigallocatechin, (-)-epicatechin gallate, and epicatechin have good inhibitory effect on lipase (% of inhibition higher than 40.0%). Besides, the natural product extracts of Galla Chinensis, lemon, and Rhei Radix et Rhizoma have a good inhibitory effect on lipase with % of inhibition of (97.5 ± 0.6)%, (88.1 ± 0.7)%, and (79.1 ± 1.6)%, respectively. Finally, the binding sites and modes of six small-molecule compounds on lipase were investigated by the molecular docking study. The results show that the developed PGM method is an effective approach for the discovery of potential lipase inhibitors.
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Alkhashrom, Sewar, Jintawee Kicuntod, Sigrun Häge, Johannes Schweininger, Yves A. Muller, Peter Lischka, Manfred Marschall, and Jutta Eichler. "Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors." Viruses 13, no. 3 (March 12, 2021): 471. http://dx.doi.org/10.3390/v13030471.
Abstract:
Nuclear egress is an essential process in the replication of human cytomegalovirus (HCMV), as it enables the migration of newly formed viral capsids from the nucleus into the cytoplasm. Inhibition of the HCMV core nuclear egress complex (core NEC), composed of viral proteins pUL50 and pUL53, has been proposed as a potential new target for the treatment of HCMV infection and disease. Here, we present a new type of small molecule inhibitors of HCMV core NEC formation, which inhibit the pUL50-pUL53 interaction at nanomolar concentrations. These inhibitors, i.e., verteporfin and merbromin, were identified through the screening of the Prestwick Chemical Library® of approved drug compounds. The inhibitory effect of merbromin is both compound- and target-specific, as no inhibition was seen for other mercury-organic compounds. Furthermore, merbromin does not inhibit an unrelated protein–protein interaction either. More importantly, merbromin was found to inhibit HCMV infection of cells in three different assays, as well as to disrupt HCMV NEC nuclear rim formation. Thus, while not being an ideal drug candidate by itself, merbromin may serve as a blueprint for small molecules with high HCMV core NEC inhibitory potential, as candidates for novel anti-herpesviral drugs.
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Yang, Cheng-Wei, Yung-Ning Yang, Po-Huang Liang, Chi-Min Chen, Wei-Liang Chen, Hwan-You Chang, Yu-Sheng Chao, and Shiow-Ju Lee. "Novel Small-Molecule Inhibitors of Transmissible Gastroenteritis Virus." Antimicrobial Agents and Chemotherapy 51, no. 11 (August 20, 2007): 3924–31. http://dx.doi.org/10.1128/aac.00408-07.
Abstract:
ABSTRACT We used swine testicle (ST) cells infected with transmissible gastroenteritis virus (TGEV) and an indirect immunofluorescent assay with antibodies against TGEV spike and nucleocapsid proteins to screen small-molecule compounds that inhibit TGEV replication. Analogues of initial hits were collected and subjected to a 3CL protease (3CLpro) inhibition assay with recombinant 3CLpro and a fluorogenic peptide substrate. A series of benzothiazolium compounds were found to have inhibitory activity against TGEV 3CLpro and to exert anti-TGEV activities in terms of viral protein and RNA replication in TGEV-infected ST cells, with consequent protection of TGEV-infected ST cells from cytopathic effect by blocking the activation of caspase-3.
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Liargkova, Thalia, Nikolaos Eleftheriadis, Frank Dekker, Efstathia Voulgari, Constantinos Avgoustakis, Marina Sagnou, Barbara Mavroidi, Maria Pelecanou, and Dimitra Hadjipavlou-Litina. "Small Multitarget Molecules Incorporating the Enone Moiety." Molecules 24, no. 1 (January 7, 2019): 199. http://dx.doi.org/10.3390/molecules24010199.
Abstract:
Chalcones represent a class of small drug/druglike molecules with different and multitarget biological activities. Small multi-target drugs have attracted considerable interest in the last decade due their advantages in the treatment of complex and multifactorial diseases, since “one drug-one target” therapies have failed in many cases to demonstrate clinical efficacy. In this context, we designed and synthesized potential new small multi-target agents with lipoxygenase (LOX), acetyl cholinesterase (AChE) and lipid peroxidation inhibitory activities, as well as antioxidant activity based on 2-/4- hydroxy-chalcones and the bis-etherified bis-chalcone skeleton. Furthermore, the synthesized molecules were evaluated for their cytotoxicity. Simple chalcone b4 presents significant inhibitory activity against the 15-human LOX with an IC50 value 9.5 µM, interesting anti-AChE activity, and anti-lipid peroxidation behavior. Bis-etherified chalcone c12 is the most potent inhibitor of AChE within the bis-etherified bis-chalcones followed by c11. Bis-chalcones c11 and c12 were found to combine anti-LOX, anti-AchE, and anti-lipid peroxidation activities. It seems that the anti-lipid peroxidation activity supports the anti-LOX activity for the significantly active bis-chalcones. Our circular dichroism (CD) study identified two structures capable of interfering with the aggregation process of Aβ. Compounds c2 and c4 display additional protective actions against Alzheimer’s disease (AD) and add to the pleiotropic profile of the chalcone derivatives. Predicted results indicate that the majority of the compounds with the exception of c11 (144 Å) can cross the Blood Brain Barrier (BBB) and act in CNS. The results led us to propose new leads and to conclude that the presence of a double enone group supports better biological activities.
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Zhang, Yan, and Niefang Yu. "Design, Synthesis and Biological Evaluation: 5-amino-1H-pyrazole-1- carbonyl derivatives as FGFR Inhibitors." Letters in Drug Design & Discovery 17, no. 11 (October 23, 2020): 1330–41. http://dx.doi.org/10.2174/1570180817999200608140628.
Abstract:
Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration, and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity. Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized, and evaluated as FGFR inhibitors. Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests were carried out to observe the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines (SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with the corresponding protein kinase. Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good anti-proliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM, and potently inhibited the SNU-16 and MCF-7 cancer cells with IC50 values of 0.71 1.26 μM, respectively. And 8e inhibited the growth of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions were quite similar in the molecular models between generated compounds and Debio-1347 with the FGFR1. Conclusion: According to the experimental findings, 5-amino-1H-pyrazole-1-carbonyl might serve as a promising template of an FGFR inhibitor.