Virtual Screening and Molecular Docking Studies for Discovery of Potential RNA-Dependent RNA Polymerase Inhibitors

Mohammed Y Ghazwani,Abdulrahman A Almehizia,Abdulrahim R Hakami,Hamad M Alkahtani,Ahmed H Bakheit

doi:10.3390/cryst11050471

Mohammed Y Ghazwani, Abdulrahman A Almehizia + Show 3 more

Open Access

https://doi.org/10.3390/cryst11050471

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Abstract

The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Globally, this pandemic has affected over 111 million individuals and posed many health and economic challenges. Much research effort is dedicated to discovering new treatments to address the associated challenges and restrict the spread of SARS-CoV-2. Since SARS-CoV-2 is a positive-strand RNA virus, its replication requires the viral RNA-dependent RNA polymerase (RdRp) enzyme. In this study, we report the discovery of new potential RdRp enzyme inhibitors based on computer modeling and simulation methodologies. The antiviral ZINC database was utilized for covalent docking virtual screening followed by molecular inter-action analyses based on reported hot spots within the RdRp binding pocket (PDB: 7BV2). Eleven molecules, ZINC000014944915, ZINC000027556215, ZINC000013556344, ZINC000003589958, ZINC000003833965, ZINC000001642252, ZINC000028525778, ZINC000027557701, ZINC000013781295, ZINC000001651128 and ZINC000013473324, were shown to have the highest binding interactions. These molecules were further assessed by molecular dynamics (MD) simu-lations and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies. The results showed that all 11 molecules except ZINC000027557701 formed stable complexes with the viral RdRp and fell within the accepted ADMET parameters. The identified molecules can be used to design future potential RdRp inhibitors.

Highlights

In December of 2019, the first cases of a new respiratory disease were reported inWuhan, China
The term Coronavirus Disease 2019 (COVID-19) was assigned to the pandemic, and its causative agent was identified as a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3]
ZINC antiviral compounds were used for covalent docking virtual screening

Summary

Introduction

In December of 2019, the first cases of a new respiratory disease were reported inWuhan, China. In December of 2019, the first cases of a new respiratory disease were reported in. (COVID-19) was assigned to the pandemic, and its causative agent was identified as a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3]. The COVID-19 virus is a new member of the Betacoronavirus genus, which includes severe acute respiratory syndrome-related coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and various bat coronaviruses [4]. SARS-CoV-2 has been linked to an elevated risk of human-to-human transmission. This is demonstrated by the finding that the SARS-CoV-2 spike protein has a greater affinity for human host cells [5,6,7]

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