Dataset Information

Pyridine Carboxamides: Potent Palm Site Inhibitors of HCV NS5B Polymerase.

ABSTRACT: Pyridine carboxamide-based inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified and optimized to a variety of topologically related scaffolds. In particular, the 2-methyl nicotinic acid scaffold was developed into inhibitors with improved biochemical (IC50-GT1b = 0.014 ?M) and cell-based HCV replicon potency (EC50-GT1b = 0.7 ?M). Biophysical and biochemical characterization identified this novel series of compounds as palm site binders to HCV polymerase.

SUBMITTER: Cheng CC

PROVIDER: S-EPMC4007899 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other

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Publications

Pyridine Carboxamides: Potent Palm Site Inhibitors of HCV NS5B Polymerase.

Cheng Cliff C CC Huang Xiaohua X Shipps Gerald W GW Wang Yu-Sen YS Wyss Daniel F DF Soucy Kyle A KA Jiang Chuan-Kui CK Agrawal Sony S Ferrari Eric E He Zhiqing Z Huang H-C HC

ACS medicinal chemistry letters 20100817 9

Pyridine carboxamide-based inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified and optimized to a variety of topologically related scaffolds. In particular, the 2-methyl nicotinic acid scaffold was developed into inhibitors with improved biochemical (IC50-GT1b = 0.014 μM) and cell-based HCV replicon potency (EC50-GT1b = 0.7 μM). Biophysical and biochemical characterization identified this novel series of compounds as palm site binders to HCV polymerase. ...[more]

PMID: 24900232

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Project description:Corona Virus 2019 Disease (COVID-19) is a rapidly emerging pandemic caused by a newly discovered beta coronavirus, called Sever Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2). SARS CoV-2 is an enveloped, single stranded RNA virus that depends on RNA-dependent RNA polymerase (RdRp) to replicate. Therefore, SARS CoV-2 RdRp is considered as a promising target to cease virus replication. SARS CoV-2 polymerase shows high structural similarity to Hepatitis C Virus-1b genotype (HCV-1b) polymerase. Arising from the high similarity between SARS CoV-2 RdRp and HCV NS5B, we utilized the reported small-molecule binders to the palm subdomain of HCV NS5B (genotype 1b) to generate a high-quality DEKOIS 2.0 benchmark set and conducted a benchmarking analysis against HCV NS5B. The three highly cited and publicly available docking tools AutoDock Vina, FRED and PLANTS were benchmarked. Based on the benchmarking results and analysis via pROC-Chemotype plot, PLANTS showed the best screening performance and can recognize potent binders at the early enrichment. Accordingly, we used PLANTS in a prospective virtual screening to repurpose both the FDA-approved drugs (DrugBank) and the HCV-NS5B palm subdomain binders (BindingDB) for SARS CoV-2 RdRp palm subdomain. Further assessment by molecular dynamics simulations for 50 ns recommended diosmin (from DrugBank) and compound 3 (from BindingDB) to be the best potential binders to SARS CoV-2 RdRp palm subdomain. The best predicted compounds are recommended to be biologically investigated against COVID-19. In conclusion, this work provides in-silico analysis to propose possible SARS CoV-2 RdRp palm subdomain binders recommended as a remedy for COVID-19. Up-to-our knowledge, this study is the first to propose binders at the palm subdomain of SARS CoV2 RdRp. Furthermore, this study delivers an example of how to make use of a high quality custom-made DEKOIS 2.0 benchmark set as a procedure to elevate the virtual screening success rate against a vital target of the rapidly emerging pandemic.

Dataset Information

Pyridine Carboxamides: Potent Palm Site Inhibitors of HCV NS5B Polymerase.

Publications

Pyridine Carboxamides: Potent Palm Site Inhibitors of HCV NS5B Polymerase.

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