Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Abstract

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods, Acta Pharmaceutica Sinica B, https://doi. Graphical abstractTwenty structures including 19 SARS-CoV-2 targets and 1 human target were built by homology modeling. Library of ZINC drug database, natural products, 78 anti-viral drugs were screened against these targets plus human ACE2. This study provides drug repositioning candidates and targets for further in vitro and in vivo studies of SARS-CoV-2. (Mengzhu Zheng), xingzhouli@aliyun.com (Xingzhou Li). † These authors made equal contributions to this work.Abstract SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study

“…After model validation, J o u r n a l P r e -p r o o f molecular docking was performed to test several direct-acting antiviral (DAA) drugs against SARS-CoV-2 RdRp, including 5 FDA-approved medications used to treat HCV, the human immunodeficiency virus (HIV), and the Ebola virus; 13 compounds in clinical trials against HCV; and two negative control compounds, in addition to the physiological nucleotides GTP, CTP, UTP, and ATP. The results were promising and suggest possible inhibition from the currently available therapeutics against the newly emerged coronavirus (Wu et al , 2020).…”

Lack of Antiviral Activity of Darunavir against SARS-CoV-2

“…Several publications describe in silico docking experiments on the main coronavirus protease that specifically focus on or include DRV (17)(18)(19)(20)(21). Although these studies suggest DRV as a candidate for further investigation, such promising docking results could not be reproduced in our in silico docking studies.…”

Identification of potential treatments for COVID-19 through artificial intelligence-enabled phenomic analysis of human cells infected with SARS-CoV-2

“…Almitrine is a respiratory stimulant used in acute respiratory failure such as chronic obstructive pulmonary disease (COPD) that is available in Europe, but not currently available in the US 14 ( Figure 2g ). Recent structure-based computational studies hypothesized that almitrine binds to the SARS-CoV-2 main viral proteinase (Mpro, or 3CLpro), an important viral target given the necessity of this protein for viral replication [15][16][17] . Our results demonstrate for the first time activity of almitrine in human cells infected with SARS-CoV-2, suggesting almitrine may represent a novel SARS-CoV-2 protease-targeting antiviral.…”