9BBP

SARS-CoV-2 Mpro in complex with compound 12d inhibitor

これはPDB形式変換不可エントリーです。

9BBP の概要

• エントリーDOI: 10.2210/pdb9bbp/pdb
• 分子名称: 3C-like proteinase nsp5, GLYCINE, VALINE, ... (7 entities in total)
• 機能のキーワード: protease, inhibitor, viral protein, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34773.64

構造登録者

Afsar, M.,Bury, P.,Olsen, S.K. (登録日: 2024-04-07, 公開日: 2025-04-16, 最終更新日: 2026-04-29)

主引用文献

Clyde-Allen, E.,Zmudzinski, M.,Afsar, M.,James, C.,Nayak, A.,Nayak, D.,Dos Santos Bury, P.,Jochmans, D.,Neyts, J.,Scott, C.J.,Olsen, S.K.,Drag, M.,Williams, R.
Identification and Exploration of a Series of SARS-Cov‐2 M Pro Cyano-Based Inhibitors Revealing Ortho-Substitution Effects within the P3 Biphenyl Group.
Acs Med.Chem.Lett., 16:1935-1945, 2025

PubMed Abstract: Starting from a simple scaffold hopping exercise based on our previous exploration of cysteine protease inhibitors against legumain, compound was identified as a starting point for the development of a SARS-CoV-2 main protease (M) inhibitor. Compound displayed submicromolar biochemical potency in the ultrasensitive assay developed by Drag and co-workers. Through an iterative structure-activity relationship campaign, we discovered an unexpected improvement in both biochemical and cellular potency through the incorporation of an ortho substituent within the P3 benzamide. X-ray crystallography revealed that incorporation of the ortho substituent caused a subtle but important binding enhancement of the P1 glutamate group within the M S1 pocket. While incorporation of the ortho substituent improved the potency, the off-target selectivity against a panel of cysteine proteases and cell activity remained suboptimal. Further scanning of the P2 core revealed that incorporation of the 3.1.0 proline could address these issues and afford compound , a highly potent and cellularly active M inhibitor.

PubMed: 41089474
DOI: 10.1021/acsmedchemlett.5c00301

実験手法

X-RAY DIFFRACTION (1.81 Å)