7LKR

1.65 A resolution structure of SARS-CoV-2 3CL protease in complex with inhibitor 2a

7LKR の概要

• エントリーDOI: 10.2210/pdb7lkr/pdb
• 分子名称: 3C-like proteinase, (1R,2S)-2-((S)-2-(((((1R,3s,5S)-bicyclo[3.3.1]nonan-3-yl)methoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, (1S,2S)-2-((S)-2-(((((1R,3s,5S)-bicyclo[3.3.1]nonan-3-yl)methoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, ... (7 entities in total)
• 機能のキーワード: covid-19, protease, severe acute respiratory syndrome coronavirus 2, sars-cov-2 3cl protease inhhibitors, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70458.49

構造登録者

Lovell, S.,Kashipathy, M.M.,Battaile, K.P.,Chamandi, S.D.,Rathnayake, A.D.,Nguyen, H.N.,Baird, M.A.,Kim, Y.,Shadipeni, N.,Chang, K.O.,Groutas, W.C. (登録日: 2021-02-02, 公開日: 2021-02-17, 最終更新日: 2024-10-30)

主引用文献

Dampalla, C.S.,Kim, Y.,Bickmeier, N.,Rathnayake, A.D.,Nguyen, H.N.,Zheng, J.,Kashipathy, M.M.,Baird, M.A.,Battaile, K.P.,Lovell, S.,Perlman, S.,Chang, K.O.,Groutas, W.C.
Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease.
J.Med.Chem., 64:10047-10058, 2021

PubMed Abstract: A series of nondeuterated and deuterated dipeptidyl aldehyde and masked aldehyde inhibitors that incorporate in their structure a conformationally constrained cyclohexane moiety was synthesized and found to potently inhibit severe acute respiratory syndrome coronavirus-2 3CL protease in biochemical and cell-based assays. Several of the inhibitors were also found to be nanomolar inhibitors of Middle East respiratory syndrome coronavirus 3CL protease. The corresponding latent aldehyde bisulfite adducts were found to be equipotent to the precursor aldehydes. High-resolution cocrystal structures confirmed the mechanism of action and illuminated the structural determinants involved in binding. The spatial disposition of the compounds disclosed herein provides an effective means of accessing new chemical space and optimizing pharmacological activity. The cellular permeability of the identified inhibitors and lack of cytotoxicity warrant their advancement as potential therapeutics for COVID-19.

PubMed: 34213885
DOI: 10.1021/acs.jmedchem.1c00319

実験手法

X-RAY DIFFRACTION (1.65 Å)