Authors
Clyde, Austin; Galanie, Stephanie; Kneller, Daniel; Ma, Heng; Babuji, Yadu; Blaiszik, Ben; Brace, Alexander; Brettin, Thomas; Chard, Kyle; Chard, Ryan; Coates, Leighton; Foster, Ian; Hauner, Darin; Kertesz, Vilmos; Kumar, Neeraj; Lee, Hyungro ; Li, Zhuozhao; Merzky, Andre; Schmidt, Jurgen; Tan, Li; Titov, Mikhail; Trifan, Anda; Turilli, Matteo; Van Dam, H. J. J.; Chennubhotla, Chakra; Jha, Shantenu; Kovalevsky, Andrey; Ramanathan, Arvind; Head, Martha; Stevens, Rick
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 (M-pro) 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 M-pro inhibitor with an inhibition constant (K-i) of 2.9 mu M (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 M-pro forming stable hydrogen bond and hydrophobic interactions. We then used multiple its-time scale molecular dynamics (MD) simulations and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by M-pro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits M-pro and offers a springboard for further therapeutic design.