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

TLDR

SARS‑CoV‑2 has caused widespread infections and deaths, and with no approved therapies, drug repositioning is urgently needed to address the rapid emergence of infectious diseases. This study aims to identify new lead compounds and targets for SARS‑CoV‑2, inform ongoing clinical trials, and propose drug‑repositioning strategies. The authors performed a comprehensive structural analysis of SARS‑CoV‑2 proteins, built 19 homology models, and screened 21 viral and human targets against ZINC and natural product libraries, also compiling a database of 78 antiviral drugs. The screening identified promising interactions with key viral proteins such as 3CLpro, Spike, RdRp, and PLpro, and predicted potential drug–target pairs for further investigation.

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.