Analyzing 3D structures of the SARS-CoV-2 main protease reveals structural features of ligand binding for COVID-19 drug discovery

Liang Xu; Ru Chen; Jie Liu; Tucker A Patterson; Huixiao Hong

doi:10.1016/j.drudis.2023.103727

Analyzing 3D structures of the SARS-CoV-2 main protease reveals structural features of ligand binding for COVID-19 drug discovery

Drug Discov Today. 2023 Oct;28(10):103727. doi: 10.1016/j.drudis.2023.103727. Epub 2023 Jul 27.

Authors

Liang Xu¹, Ru Chen², Jie Liu¹, Tucker A Patterson¹, Huixiao Hong³

Affiliations

¹ National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
² Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
³ National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: Huixiao.Hong@fda.hhs.gov.

PMID: 37516343
DOI: 10.1016/j.drudis.2023.103727

Abstract

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) main protease has an essential role in viral replication and has become a major target for coronavirus 2019 (COVID-19) drug development. Various inhibitors have been discovered or designed to bind to the main protease. The availability of more than 550 3D structures of the main protease provides a wealth of structural details on the main protease in both ligand-free and ligand-bound states. Therefore, we examined these structures to ascertain the structural features for the role of the main protease in the cleavage of polyproteins, the alternative conformations during main protease maturation, and ligand interactions in the main protease. The structural features unearthed could promote the development of COVID-19 drugs targeting the SARS-CoV-2 main protease.

Keywords: COVID-19; SARS-CoV-2; conformations; drug discovery and design; inhibitor; main protease; protein–ligand interactions.

Published by Elsevier Ltd.

Publication types

Review

MeSH terms

Antiviral Agents / chemistry
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
COVID-19*
Coronavirus 3C Proteases
Drug Discovery
Humans
Ligands
Molecular Docking Simulation
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
Protease Inhibitors / therapeutic use
SARS-CoV-2* / metabolism
Viral Nonstructural Proteins / metabolism

Substances

3C-like proteinase, SARS-CoV-2
Protease Inhibitors
Ligands
Viral Nonstructural Proteins
Coronavirus 3C Proteases
Antiviral Agents