7S3K

Room temperature X-ray structure of SARS-CoV-2 main protease in complex with compound Z1530718726

7S3K の概要

• エントリーDOI: 10.2210/pdb7s3k/pdb
• 分子名称: 3C-like proteinase, 2-(5-chloro-2-methoxyphenyl)-N-(isoquinolin-4-yl)acetamide (3 entities in total)
• 機能のキーワード: enzyme-inhibitor complex, cysteine protease, homodimer, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34152.32

構造登録者

Kovalevsky, A.,Kneller, D.W.,Coates, L. (登録日: 2021-09-07, 公開日: 2021-09-15, 最終更新日: 2023-10-18)

主引用文献

Glaser, J.,Sedova, A.,Galanie, S.,Kneller, D.W.,Davidson, R.B.,Maradzike, E.,Del Galdo, S.,Labbe, A.,Hsu, D.J.,Agarwal, R.,Bykov, D.,Tharrington, A.,Parks, J.M.,Smith, D.M.A.,Daidone, I.,Coates, L.,Kovalevsky, A.,Smith, J.C.
Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor.
Acs Pharmacol Transl Sci, 5:255-265, 2022

PubMed Abstract: Inhibition of the SARS-CoV-2 main protease (M) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of M. Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 μM. Among these, four compounds with IC values around 1 μM were found. Interestingly, despite the large search space, the isoquinolone motif was conserved in each of these four strongest binders. Room-temperature X-ray structures of co-crystallized protein-inhibitor complexes were determined up to 1.9 Å resolution for two of these compounds as well as one of the stronger inhibitors in the original isoquinoline series, revealing essential interactions with the binding site and water molecules. Molecular dynamics simulations and quantum chemical calculations further elucidate the binding interactions as well as electrostatic effects on ligand binding. The results help explain the strength of this new non-covalent scaffold for M inhibition and inform lead optimization efforts for this series, while demonstrating the effectiveness of a high-throughput computational approach to expanding a pharmacophore library.

PubMed: 35434531
DOI: 10.1021/acsptsci.2c00026

実験手法

X-RAY DIFFRACTION (1.9 Å)