7LMF

SARS-CoV-2 3CLPro in complex with 2-(benzotriazol-1-yl)-N-[4-(1H-imidazol-4-yl)phenyl]-N-(3-thienylmethyl)acetamide

7LMF の概要

• エントリーDOI: 10.2210/pdb7lmf/pdb
• 分子名称: 3C-like proteinase, 2-(benzotriazol-1-yl)-~{N}-[4-(1~{H}-imidazol-4-yl)phenyl]-~{N}-(thiophen-3-ylmethyl)ethanamide (3 entities in total)
• 機能のキーワード: 3clpro, sars-cov-2 main protease, sars-cov-2 3clpro, inhibitor complex, protease, viral protein, 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: 2
• 化学式量合計: 68480.06

構造登録者

Goins, C.M.,Arya, T.,Macdonald, J.D.,Stauffer, S.R. (登録日: 2021-02-05, 公開日: 2021-08-11, 最終更新日: 2023-10-18)

主引用文献

Han, S.H.,Goins, C.M.,Arya, T.,Shin, W.J.,Maw, J.,Hooper, A.,Sonawane, D.P.,Porter, M.R.,Bannister, B.E.,Crouch, R.D.,Lindsey, A.A.,Lakatos, G.,Martinez, S.R.,Alvarado, J.,Akers, W.S.,Wang, N.S.,Jung, J.U.,Macdonald, J.D.,Stauffer, S.R.
Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CL pro ).
J.Med.Chem., 65:2880-2904, 2022

PubMed Abstract: Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CL enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CL inhibitors. DMPK profiling highlights key areas where further optimization in the series is required to obtain useful probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

PubMed: 34347470
DOI: 10.1021/acs.jmedchem.1c00598

実験手法

X-RAY DIFFRACTION (2.2 Å)