Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188
Authors
Lockbaum, Gordon J.Reyes, Archie C.
Lee, Jeong Min
Tilvawala, Ronak
Nalivaika, Ellen A.
Ali, Akbar
Yilmaz, Nese Kurt
Thompson, Paul R
Schiffer, Celia A.
UMass Chan Affiliations
Schiffer LabThompson Lab
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2021-01-25Keywords
Covid-19ML188
Mpro
SARS-CoV-2
crystal structure
direct-acting antivirals
main protease
protease inhibitor
structure-based drug design
Enzymes and Coenzymes
Medicinal Chemistry and Pharmaceutics
Medicinal-Pharmaceutical Chemistry
Pharmaceutics and Drug Design
Structural Biology
Virology
Virus Diseases
Metadata
Show full item recordAbstract
Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (M(pro)) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 M(pro), and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 M(pro) at 2.5 microM, which is more potent than against SAR-CoV-1 M(pro). We determined the crystal structure of ML188 in complex with SARS-CoV-2 M(pro) to 2.39 A resolution. Sharing 96% sequence identity, structural comparison of the two complexes only shows subtle differences. Non-covalent protease inhibitors complement the design of covalent inhibitors against SARS-CoV-2 main protease and are critical initial steps in the design of DAAs to treat CoVID 19.Source
Lockbaum GJ, Reyes AC, Lee JM, Tilvawala R, Nalivaika EA, Ali A, Kurt Yilmaz N, Thompson PR, Schiffer CA. Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188. Viruses. 2021 Jan 25;13(2):174. doi: 10.3390/v13020174. PMID: 33503819. Link to article on publisher's site
DOI
10.3390/v13020174Permanent Link to this Item
http://hdl.handle.net/20.500.14038/27380PubMed ID
33503819Related Resources
Rights
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.3390/v13020174
Scopus Count
Except where otherwise noted, this item's license is described as Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).