﻿Molecular docking and dynamic simulations study for repurposing of multitarget coumarins against SARS-CoV-2 main protease, papain-like protease and RNA-dependent RNA polymerase

Amer Ali Abd El-Hafeez,Abdullah A Assiri,Moteb Khobrani,Mai E Shoman,Ahmed R N Ibrahim,Sultan S Al Thagfan,Eman M Othman

doi:10.3897/pharmacia.69.e77021

Abstract

Proteases and RNA-Dependent RNA polymerase, major enzymes which are essential targets involved in the life and replication of SARS-CoV-2. This study aims at in silico examination of the potential ability of coumarins and their derivatives to inhibit the replication of SARS-Cov-2 through multiple targets, including the main protease, papain-like protease and RNA-Dependent RNA polymerase. Several coumarins as biologically active compounds were studied, including coumarin antibiotics and some naturally reported antiviral coumarins. Aminocoumarin antibiotics, especially coumermycin, showed a high potential to bind to the enzymes’ active site, causing possible inhibition and termination of viral life. They demonstrate the ability to bind to residues essential for triggering the crucial cascades within the viral cell. Molecular dynamics simulations for 50 ns supported these data pointing out the formation of rigid, stable Coumermycin/enzyme complexes. These findings strongly suggest the possible use of Coumermycin, Clorobiocin or Novobiocin in the fight against COVID-19, but biological evidence is still required to support such suggestions.

Highlights

COVID-19, a disease caused by the newly emerged virus SARS-CoV-2 of the coronavirus family, was declared a pandemic worldwide on 11th March 2020
Based on the rich literature supporting the presence of coumarins as promising antiviral candidates, we report the virtual docking of selected coumarin drugs, including coumarin antibiotics, other famous coumarin drugs (Figs 1 and 2), and some natural coumarins previously reported as antiviral agents (Hassan et al 2016) (Fig. 3) into the active site of SARS-CoV-2 main protease to introduce coumarins as a potential therapeutic strategy against COVID-19
For main protease of the virus (Mpro) enzyme (PDB: 5RH4, 1.34Ao), the structure was identified by X-ray diffraction as the crystal structure of SARS-CoV-2 main protease in complex with Z15304250633; for Papain-like protease

Summary

Introduction

COVID-19, a disease caused by the newly emerged virus SARS-CoV-2 of the coronavirus family, was declared a pandemic worldwide on 11th March 2020. From all the essential enzymes, we selected the main protease of the virus (Mpro), papain-like cysteine protease (PLpro), and RNA-dependent RNA polymerase (RdRp). Several studies were performed to allocate a potential inhibitor for such enzyme and potentially end the viral life in the human body (Kandeel and Al-Nazawi 2020; Peele et al 2020; Tachoua et al 2020). Among those studies, most used virtual docking and structure-based analysis (Hall and Ji 2020; Kumar et al 2020; Rahman et al 2020; Selvaraj et al 2020; Yu et al 2020)

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