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In Journal of chemical information and modeling

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.

Clyde Austin, Galanie Stephanie, Kneller Daniel W, Ma Heng, Babuji Yadu, Blaiszik Ben, Brace Alexander, Brettin Thomas, Chard Kyle, Chard Ryan, Coates Leighton, Foster Ian, Hauner Darin, Kertesz Vlimos, Kumar Neeraj, Lee Hyungro, Li Zhuozhao, Merzky Andre, Schmidt Jurgen G, Tan Li, Titov Mikhail, Trifan Anda, Turilli Matteo, Van Dam Hubertus, Chennubhotla Srinivas C, Jha Shantenu, Kovalevsky Andrey, Ramanathan Arvind, Head Martha S, Stevens Rick