7T49

Structure of SARS-CoV-2 3CL protease in complex with inhibitor 10c

7T49 の概要

• エントリーDOI: 10.2210/pdb7t49/pdb
• 分子名称: 3C-like proteinase, (1R,2S)-1-hydroxy-2-{[N-({[7-(methanesulfonyl)-7-azaspiro[3.5]nonan-2-yl]oxy}carbonyl)-L-leucyl]amino}-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, (1S,2S)-1-hydroxy-2-{[N-({[7-(methanesulfonyl)-7-azaspiro[3.5]nonan-2-yl]oxy}carbonyl)-L-leucyl]amino}-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, ... (4 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, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 2019-nCoV)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70524.47

構造登録者

Lovell, S.,Liu, L.,Battaile, K.P.,Chamandi, S.D.,Kim, Y.,Groutas, W.C.,Chang, K.O. (登録日: 2021-12-09, 公開日: 2021-12-22, 最終更新日: 2023-10-18)

主引用文献

Dampalla, C.S.,Rathnayake, A.D.,Galasiti Kankanamalage, A.C.,Kim, Y.,Perera, K.D.,Nguyen, H.N.,Miller, M.J.,Madden, T.K.,Picard, H.R.,Thurman, H.A.,Kashipathy, M.M.,Liu, L.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C.
Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease.
J.Med.Chem., 65:7818-7832, 2022

PubMed Abstract: The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CL) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CL that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CL and MERS-CoV 3CL that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.

PubMed: 35638577
DOI: 10.1021/acs.jmedchem.2c00224

実験手法

X-RAY DIFFRACTION (1.75 Å)