8ACD

Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the non-covalent inhibitor GA-17S

8ACD の概要

• エントリーDOI: 10.2210/pdb8acd/pdb
• 分子名称: 3C-like proteinase nsp5, (2~{S})-4-[[2,4-bis(oxidanylidene)-1~{H}-pyrimidin-6-yl]carbonyl]-1-(3,4-dichlorophenyl)-~{N}-(thiophen-2-ylmethyl)piperazine-2-carboxamide (3 entities in total)
• 機能のキーワード: sars-cov-2, main protease, non-covalent inhibitor, drug design, viral protein
• 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: 1
• 化学式量合計: 34333.92

構造登録者

Strater, N.,Muller, C.E.,Sylvester, K.,Claff, T.,Weisse, R.H.,Gao, S.,Tollefson, A.E.,Liu, X.,Zhan, P. (登録日: 2022-07-05, 公開日: 2022-09-28, 最終更新日: 2024-01-31)

主引用文献

Gao, S.,Sylvester, K.,Song, L.,Claff, T.,Jing, L.,Woodson, M.,Weisse, R.H.,Cheng, Y.,Schakel, L.,Petry, M.,Gutschow, M.,Schiedel, A.C.,Strater, N.,Kang, D.,Xu, S.,Toth, K.,Tavis, J.,Tollefson, A.E.,Muller, C.E.,Liu, X.,Zhan, P.
Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity.
J.Med.Chem., 65:13343-13364, 2022

PubMed Abstract: The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to combat the highly infectious variants. The main protease (M) is an promising target for anti-SARS-CoV-2 drug design. Here, we report the discovery of potent non-covalent non-peptide M inhibitors featuring a 1,2,4-trisubstituted piperazine scaffold. We systematically modified the non-covalent hit MCULE-5948770040 by structure-based rational design combined with multi-site binding and privileged structure assembly strategies. The optimized compound inhibits M with high potency (IC = 0.40 μM) and displays excellent antiviral activity (EC = 1.1 μM), being more potent than Remdesivir. Notably, exhibits low cytotoxicity (CC > 100 μM) and excellent target selectivity for SARS-CoV-2 M (IC > 50 μM for cathepsins B, F, K, L, and caspase 3). X-ray co-crystal structures prove that the inhibitors occupy multiple subpockets by critical non-covalent interactions. These studies may provide a basis for developing a more efficient and safer therapy for COVID-19.

PubMed: 36107752
DOI: 10.1021/acs.jmedchem.2c01146

実験手法

X-RAY DIFFRACTION (1.39 Å)