Computational Identification of Possible Allosteric Sites and Modulators of the SARS-CoV-2 Main Protease

Autor:	Debarati DasGupta, Wallace K. B. Chan, Heather A. Carlson
Rok vydání:	2022
Předmět:	SARS-CoV-2 General Chemical Engineering COVID-19 General Chemistry Molecular Dynamics Simulation Library and Information Sciences Antiviral Agents Article Computer Science Applications Molecular Docking Simulation Humans Protease Inhibitors Allosteric Site Coronavirus 3C Proteases
Zdroj:	J Chem Inf Model
ISSN:	1549-960X 1549-9596
DOI:	10.1021/acs.jcim.1c01223
Popis:	In this study, we target the main protease (M(pro)) of the SARS-CoV-2 virus as it is a crucial enzyme for viral replication. Herein, we report three plausible allosteric sites on M(pro) that can expand structure-based drug discovery efforts for new M(pro) inhibitors. To find these sites, we used mixed-solvent molecular dynamics (MixMD) simulations, an efficient computational protocol that finds binding hotspots through mapping the surface of unbound proteins with 5% cosolvents in water. We have used normal mode analysis to support our claim of allosteric control for these sites. Further, we have performed virtual screening against the sites with 361 hits from M(pro) screenings available through the National Center for Advancing Translational Sciences (NCATS). We have identified the NCATS inhibitors that bind to the remote sites better than the active site of M(pro), and we propose these molecules may be allosteric regulators of the system. After identifying our sites, new X-ray crystal structures were released that show fragment molecules in the sites we found, supporting the notion that these sites are accurate and druggable.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::607f6176275397b1bee62d95218571a4 https://doi.org/10.1021/acs.jcim.1c01223 Zobrazit plný text záznamu