Comparative assessment of RNA-dependent RNA polymerase (RdRp) inhibitors under clinical trials to control SARS-CoV2 using rigorous computational workflow.

Dweipayan Goswami

doi:10.1039/d1ra04460e

Abstract

The devastating effect of SARS-CoV2 continues and the scientific community is pursuing to find the strategy to combat the spread of the virus. The approach is adapted to target this virus with medicine in combination with existing vaccines. For this, the medications that can specifically inhibit an enzyme essential for viral replication ‘RNA-dependant-RNA polymerase (RdRp)’ of SARS-CoV2 are being developed. RdRp is the enzyme commonly found in all RNA viruses but is absent in humans. There are in total 60 different RdRp inhibitors already under clinical trials for combating other RNA viruses, which are sought to even work for SARS-CoV2. These inhibitors are classified as nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. In this study, all the known RdRp inhibitors were computationally targeted in the native form and their active form making the use of molecular docking, MM-GBSA and molecular dynamics (MD) simulations to find the top two of each nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. The results showed ribavirin 5′-triphosphate and favipiravir ribonucleoside triphosphate (favipiravir-RTP) to be the top two nucleotide analogues while pimodivir and dihydropyrazolopyridinone analogue 8d were the top two nonnucleosides/non-nucleotide analogues.

Highlights

RNA viruses are notorious and have always challenged humans by causing infections that have a history to become disastrous.[1]
If there is a structural similarity of SARS-CoV2 RNA-dependant-RNA polymerase (RdRp) with other viral RdRp, there is a high probability that an inhibitor developed for some other +ssRNA virus may work for the SARS-CoV2 RdRp
As RdRp is the enzyme commonly found in all RNA viruses but is absent in humans, and medications in the form of RdRp inhibitors for the other RNA viruses are already known and are currently repurposed speci cally for RdRp of SARS-CoV2

Summary

Introduction

RNA viruses are notorious and have always challenged humans by causing infections that have a history to become disastrous.[1]. SARSCoV2 belongs to a larger family of +ssRNA viruses, coronaviruses (CoV), named based on its morphology, which shows spikes on its outer surface making it resemble the sun-situated crown, the corona. These CoVs have four main phylogenetic branches based on their genetic sequences and they are, alpha (a), beta (b), gamma (g) and delta (d) CoVs. The viruses that can Department of Microbiology & Biotechnology, University School of Sciences, Gujarat University, Ahmedabad 380009, Gujarat, India. Cheng and colleagues back in 2007 said, lethal CoVs can evolve by stable genetic mutation and recombination, which is literally an ‘a ticking time bomb’ as a threat to humanity, which in turn is found to be true today.[5]

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