Identification of key interactions between SARS-CoV-2 main protease and inhibitor drug candidates

Ryunosuke Yoshino,Nobuaki Yasuo,Masakazu Sekijima

doi:10.1038/s41598-020-69337-9

Abstract

The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. SARS-CoV-2 caused a pandemic in Wuhan, China, in December 2019 and is rapidly spreading globally. It has been reported that peptide-like anti-HIV-1 drugs are effective against SARS-CoV Main protease (Mpro). Due to the close phylogenetic relationship between SARS-CoV and SARS-CoV-2, their main proteases share many structural and functional features. Thus, these drugs are also regarded as potential drug candidates targeting SARS-CoV-2 Mpro. However, the mechanism of action of SARS-CoV-2 Mpro at the atomic-level is unknown. In the present study, we revealed key interactions between SARS-CoV-2 Mpro and three drug candidates by performing pharmacophore modeling and 1 μs molecular dynamics (MD) simulations. His41, Gly143, and Glu166 formed interactions with the functional groups that were common among peptide-like inhibitors in all MD simulations. These interactions are important targets for potential drugs against SARS-CoV-2 Mpro.

Highlights

The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000
Molecular dynamics (MD) simulations, in which the dynamics of biopolymers in solution can be analyzed at the atomic level, is a typical structure-based drug discovery (SBDD) method used to predict the interaction between proteins and inhibitors[22,23,24,25,26]
We revealed important interactions for potential anti-coronavirus drugs to bind to SARS-CoV-2 Mpro by pharmacophore modeling and molecular dynamics (MD) simulations

Summary

Introduction

The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. Due to the close phylogenetic relationship between SARS-CoV and SARS-CoV-2, their main proteases share many structural and functional features These drugs are regarded as potential drug candidates targeting SARS-CoV-2 Mpro. His[41], Gly[143], and Glu[166] formed interactions with the functional groups that were common among peptide-like inhibitors in all MD simulations These interactions are important targets for potential drugs against SARS-CoV-2 Mpro. The Republic of Korea has reported more than 4,200 cases and 22 deaths, which accounts for more than half of the cases of COVID-19 reported outside C hina[5] To contain this virus outbreak, it is important to identify effective therapeutic drugs immediately[6]. By modeling the complex structure of SARS-CoV-2 M pro and inhibitors using information on the known structure of SARS-CoV-Mpro and peptide-like inhibitors, it is possible to analyze the characteristics of functional groups required for the molecular recognition of ligands by SARS-CoV-2 M pro

Methods

Results

Conclusion