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Department of Biochemistry and Molecular Pharmacology; Thompson Lab; Schiffer Lab

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Enzymes and Coenzymes | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Pharmaceutics and Drug Design | Structural Biology | Virology | Virus Diseases


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.


Covid-19, ML188, Mpro, SARS-CoV-2, crystal structure, direct-acting antivirals, main protease, protease inhibitor, structure-based drug design

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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 (

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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

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.