Abstract
The unprecedented pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening global health. SARS-CoV-2 has caused severe disease with significant mortality since December 2019. The enzyme chymotrypsin-like protease (3CLpro) or main protease (Mpro) of the virus is considered to be a promising drug target due to its crucial role in viral replication and its genomic dissimilarity to human proteases. In this study, we implemented a structure-based virtual screening (VS) protocol in search of compounds that could inhibit the viral Mpro. A library of >eight hundred compounds was screened by molecular docking into multiple structures of Mpro, and the result was analyzed by consensus strategy. Those compounds that were ranked mutually in the ‘Top-100’ position in at least 50% of the structures were selected and their analogous binding modes predicted simultaneously in all the structures were considered as bioactive poses. Subsequently, based on the predicted physiological and pharmacokinetic behavior and interaction analysis, eleven compounds were identified as ‘Hits’ against SARS-CoV-2 Mpro. Those eleven compounds, along with the apo form of Mpro and one reference inhibitor (X77), were subjected to molecular dynamic simulation to explore the ligand-induced structural and dynamic behavior of Mpro. The MM-GBSA calculations reflect that eight out of eleven compounds specifically possess high to good binding affinities for Mpro. This study provides valuable insights to design more potent and selective inhibitors of SARS-CoV-2 Mpro.
Highlights
SARS-CoV-2 belongs to the β coronavirus subgroup of the Coronaviridae family and was found to be related to acute respiratory syndrome coronavirus (SARS-CoV) [6], which previously emerged in China in February 2003 and caused an outbreak in China and spread to several other countries [5,6]
The results indicate that dynamic variability and conformational changes were caused by small inhibitors, revealing the affinity of ligands toward main protease (Mpro)
We have employed an efficient structure-based virtual screening protocol to search for novel inhibitors of SARS-CoV-2
Summary
The current global pandemic, so called COVID-19 (COronaVIrus Disease 2019), has spread rapidly since it initially emerged in Wuhan in China, in late 2019 [1,2,3,4]. The virus called ‘severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)’ is responsible for the outbreak of this pandemic [5]. SARS-CoV-2 belongs to the β coronavirus subgroup of the Coronaviridae family and was found to be related to acute respiratory syndrome coronavirus (SARS-CoV) [6], which previously emerged in China in February 2003 and caused an outbreak in China and spread to several other countries [5,6]. SARS-CoV-2 infects humans by causing an atypical pneumonia, which possesses specific mild to severe symptoms including dry cough, fatigue, fever, shortness of breath, severe progressive pneumonia, multiorgan failure, and eventually death [1].
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