9HAJ

Structure of compound 1 bound to SARS-CoV-2 main protease

This is a non-PDB format compatible entry.

Summary for 9HAJ

• Entry DOI: 10.2210/pdb9haj/pdb
• Descriptor: 3C-like proteinase nsp5, (5~{R})-4-[(4-bromanyl-2-ethyl-phenyl)methyl]-1-(5-chloranylpyridin-3-yl)carbonyl-~{N}-ethyl-1,4-diazepane-5-carboxamide, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: inhibitor, docking, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68780.38

Authors

Mac Sweeney, A.,Hazemann, J. (deposition date: 2024-11-04, release date: 2025-03-05, Last modification date: 2025-05-07)

Primary citation

Hazemann, J.,Kimmerlin, T.,Mac Sweeney, A.,Bourquin, G.,Lange, R.,Ritz, D.,Richard-Bildstein, S.,Regeon, S.,Czodrowski, P.
Accelerating the Hit-To-Lead Optimization of a SARS-CoV-2 Mpro Inhibitor Series by Combining High-Throughput Medicinal Chemistry and Computational Simulations.
J.Med.Chem., 68:8269-8294, 2025

PubMed Abstract: In this study, we performed the hit-to-lead optimization of a SARS-CoV-2 Mpro diazepane hit (identified by computational methods in a previous work) by combining computational simulations with high-throughput medicinal chemistry (HTMC). Leveraging the 3D structural information of Mpro, we refined the original hit by targeting the S1 and S2 binding pockets of the protein. Additionally, we identified a novel exit vector pointing toward the S1' pocket, which significantly enhanced the binding affinity. This strategy enabled us to transform, rapidly with a limited number of compounds synthesized, a 14 μM hit into a potent 16 nM lead compound, for which key pharmacological properties were subsequently evaluated. This result demonstrated that combining computational technologies such as machine learning, molecular docking, and molecular dynamics simulation with HTMC can efficiently accelerate hit identification and subsequent lead generation.

PubMed: 40186586
DOI: 10.1021/acs.jmedchem.4c02941

Experimental method

X-RAY DIFFRACTION (1.276 Å)