7LTJ

Room-temperature X-ray structure of SARS-CoV-2 main protease (3CL Mpro) in complex with a non-covalent inhibitor Mcule-5948770040

Summary for 7LTJ

• Entry DOI: 10.2210/pdb7ltj/pdb
• Descriptor: 3C-like proteinase, 6-[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl-1~{H}-pyrimidine-2,4-dione (3 entities in total)
• Functional Keywords: cysteine protease, viral protease, sars-cov-2, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV,SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34194.75

Authors

Kovalevsky, A.,Kneller, D.W.,Coates, L. (deposition date: 2021-02-19, release date: 2021-03-03, Last modification date: 2023-10-18)

Primary citation

Clyde, A.,Galanie, S.,Kneller, D.W.,Ma, H.,Babuji, Y.,Blaiszik, B.,Brace, A.,Brettin, T.,Chard, K.,Chard, R.,Coates, L.,Foster, I.,Hauner, D.,Kertesz, V.,Kumar, N.,Lee, H.,Li, Z.,Merzky, A.,Schmidt, J.G.,Tan, L.,Titov, M.,Trifan, A.,Turilli, M.,Van Dam, H.,Chennubhotla, S.C.,Jha, S.,Kovalevsky, A.,Ramanathan, A.,Head, M.S.,Stevens, R.
High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor.
J.Chem.Inf.Model., 62:116-128, 2022

PubMed 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) 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 inhibitor with an inhibition constant () 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 M 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 M, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits M and offers a springboard for further therapeutic design.

PubMed: 34793155
DOI: 10.1021/acs.jcim.1c00851

Experimental method

X-RAY DIFFRACTION (1.8 Å)