Original article
Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase

https://doi.org/10.1016/j.jpha.2020.04.008Get rights and content
Under a Creative Commons license
open access

Highlights

  • The integrated structure-based approach identified potential inhibitors against SARS-CoV-2 proteins.

  • Structurally important binding site residues are elucidated through energy decomposition analysis.

  • The structural insights provide important information for future drug development against COVID-19.

Abstract

Recently emerged SARS-CoV-2 caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear, threatening global health safety. To date, no licensed antiviral drugs or vaccines are available against COVID-19 although several clinical trials are under way to test possible therapies. During this urgent situation, computational drug discovery methods provide an alternative to tiresome high-throughput screening, particularly in the hit-to-lead-optimization stage. Identification of small molecules that specifically target viral replication apparatus has indicated the highest potential towards antiviral drug discovery. In this work, we present potential compounds that specifically target SARS-CoV-2 vital proteins, including the main protease, Nsp12 RNA polymerase and Nsp13 helicase. An integrative virtual screening and molecular dynamics simulations approach has facilitated the identification of potential binding modes and favourable molecular interaction profile of corresponding compounds. Moreover, the identification of structurally important binding site residues in conserved motifs located inside the active site highlights relative importance of ligand binding based on residual energy decomposition analysis. Although the current study lacks experimental validation, the structural information obtained from this computational study has paved way for the design of targeted inhibitors to combat COVID-19 outbreak.

Keywords

SARS-CoV-2
COVID-19 outbreak
CoV-Mpro
CoV-Nsp12 polymerase
CoV-Nsp13 helicase

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Peer review under responsibility of Xi'an Jiaotong University.