Drug design and repurposing with DockThor-VS web server focusing on SARS-CoV-2 therapeutic targets and their non-synonym variants

Isabella A Guedes,Vivian Medeiros,Laurent E Dardenne,Karina B Dos Santos,Ana L M Karl,Gregório K Rocha,Marcelo M Galheigo,Helio J C Barbosa,Marisa F Nicolás,Fábio L Custódio,Iury M Teixeira,Leon S C Costa,Eduardo Krempser

doi:10.1038/s41598-021-84700-0

Abstract

The COVID-19 caused by the SARS-CoV-2 virus was declared a pandemic disease in March 2020 by the World Health Organization (WHO). Structure-Based Drug Design strategies based on docking methodologies have been widely used for both new drug development and drug repurposing to find effective treatments against this disease. In this work, we present the developments implemented in the DockThor-VS web server to provide a virtual screening (VS) platform with curated structures of potential therapeutic targets from SARS-CoV-2 incorporating genetic information regarding relevant non-synonymous variations. The web server facilitates repurposing VS experiments providing curated libraries of currently available drugs on the market. At present, DockThor-VS provides ready-for-docking 3D structures for wild type and selected mutations for Nsp3 (papain-like, PLpro domain), Nsp5 (Mpro, 3CLpro), Nsp12 (RdRp), Nsp15 (NendoU), N protein, and Spike. We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations to identify possible new treatments of SARS-CoV-2 infections. The DockThor-VS is freely available at www.dockthor.lncc.br.

Highlights

The COVID-19 caused by the severe acute respiratory syndrome (SARS)-CoV-2 virus was declared a pandemic disease in March 2020 by the World Health Organization (WHO)
The multi-domain non-structural protein 3 (Nsp3) is the largest protein produced by the coronavirus, comprising 16 different domains and regions that regulate viral infection, with the papain-like protease domain (PLpro) being the most widely targeted domain from non-structural proteins (Nsps)[3]
We have described our current efforts to improve and apply a virtual screening approach at the DockThor-VS platform to repurpose known drugs against six selected proteins of SARS-CoV-2

Summary

Introduction

The COVID-19 caused by the SARS-CoV-2 virus was declared a pandemic disease in March 2020 by the World Health Organization (WHO). We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations to identify possible new treatments of SARS-CoV-2 infections. All structural proteins are translated from viral subgenomic messenger RNAs (sgRNAs) produced by the replication and transcription complex (RTC), which includes both the RNA-dependent RNA polymerase (Nsp[12], RdRp)[4,10] and the 3′-5 ’exoribonuclease with a functional proofreading-repair activity (Nsp[14], ExoN)[4] Albeit their high copying fidelity, mutations in CoVs are observed as consequences of three known processes, namely (i) as lesions during the error-prone repair process; (ii) as a mechanism of RNA recombination and segment reassortment; (iii) by host-dependent RNA editing systems, such APOBECs and A DARs11. The monitoring of genomic changes in SARS-CoV-2 for identifying regions associated with drug resistance and vaccine evasion is essential in designing antiviral therapies

Methods

Results

Conclusion