8VQX

Structure of SARS-CoV-2 main protease with potent peptide aldehyde inhibitor

これはPDB形式変換不可エントリーです。

8VQX の概要

• エントリーDOI: 10.2210/pdb8vqx/pdb
• 分子名称: 3C-like proteinase nsp5, N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-1-(1H-indole-2-carbonyl)-4,4-dimethyl-L-prolinamide, SODIUM ION, ... (6 entities in total)
• 機能のキーワード: viral protein sars cov 2, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 2019-nCoV, COVID-19 virus)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36674.64

構造登録者

Dougan, D.R.,Lane, W. (登録日: 2024-01-19, 公開日: 2024-08-07, 最終更新日: 2024-10-23)

主引用文献

Carney, D.W.,Leffler, A.E.,Bell, J.A.,Chandrasinghe, A.S.,Cheng, C.,Chang, E.,Dornford, A.,Dougan, D.R.,Frye, L.L.,Grimes, M.E.,Knehans, T.,Knight, J.L.,Komandla, M.,Lane, W.,Li, H.,Newman, S.R.,Phimister, K.,Saikatendu, K.S.,Silverstein, H.,Vafaei, S.
Exploiting high-energy hydration sites for the discovery of potent peptide aldehyde inhibitors of the SARS-CoV-2 main protease with cellular antiviral activity.
Bioorg.Med.Chem., 103:117577-117577, 2024

PubMed Abstract: Small-molecule antivirals that prevent the replication of the SARS-CoV-2 virus by blocking the enzymatic activity of its main protease (Mpro) are and will be a tenet of pandemic preparedness. However, the peptidic nature of such compounds often precludes the design of compounds within favorable physical property ranges, limiting cellular activity. Here we describe the discovery of peptide aldehyde Mpro inhibitors with potent enzymatic and cellular antiviral activity. This structure-activity relationship (SAR) exploration was guided by the use of calculated hydration site thermodynamic maps (WaterMap) to drive potency via displacement of waters from high-energy sites. Thousands of diverse compounds were designed to target these high-energy hydration sites and then prioritized for synthesis by physics- and structure-based Free-Energy Perturbation (FEP+) simulations, which accurately predicted biochemical potencies. This approach ultimately led to the rapid discovery of lead compounds with unique SAR that exhibited potent enzymatic and cellular activity with excellent pan-coronavirus coverage.

PubMed: 38518735
DOI: 10.1016/j.bmc.2023.117577

実験手法

X-RAY DIFFRACTION (1.35 Å)