1. High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor
- Author
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Andre Merzky, Ryan Chard, Jurgen G. Schmidt, Zhuozhao Li, Srinivas C. Chennubhotla, Heng Ma, Li Tan, Mikhail Titov, Vlimos Kertesz, Austin Clyde, Daniel W. Kneller, Hyungro Lee, Alexander Brace, Rick Stevens, Darin Hauner, Leighton Coates, Shantenu Jha, Kyle Chard, Andrey Kovalevsky, Arvind Ramanathan, Thomas Brettin, Neeraj Kumar, Ben Blaiszik, Stephanie Galanie, Hubertus J. J. van Dam, Matteo Turilli, Martha S Head, Yadu Babuji, Ian Foster, and Anda Trifan
- Subjects
General Chemical Engineering ,medicine.medical_treatment ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Context (language use) ,Computational biology ,Molecular Dynamics Simulation ,Library and Information Sciences ,medicine.disease_cause ,Antiviral Agents ,Article ,Piperazines ,medicine ,Humans ,Protease Inhibitors ,Binding site ,Coronavirus 3C Proteases ,Coronavirus ,Orotic Acid ,Virtual screening ,Protease ,SARS-CoV-2 ,Chemistry ,COVID-19 ,General Chemistry ,Ligand (biochemistry) ,Computer Science Applications ,Molecular Docking Simulation ,Docking (molecular) - Abstract
Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel noncovalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (Mpro) by employing a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro inhibitor with an inhibition constant (Ki) of 2.9 μM (95% CI 2.2, 4.0). Furthermore, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of Mpro forming stable hydrogen bond and hydrophobic interactions. We then used multiple μs-time scale molecular dynamics (MD) simulations and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro and offers a springboard for further therapeutic design.
- Published
- 2021
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