7N8C

Joint X-ray/neutron structure of SARS-CoV-2 main protease (Mpro) in complex with Mcule5948770040

7N8C の概要

• エントリーDOI: 10.2210/pdb7n8c/pdb
• 分子名称: 3C-like proteinase, 6-[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl-1~{H}-pyrimidine-2,4-dione (3 entities in total)
• 機能のキーワード: cysteine protease, inhibitor complex, protonation states, hydrolase
• 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: 34194.75

構造登録者

Kovalevsky, A.,Kneller, D.W.,Coates, L. (登録日: 2021-06-14, 公開日: 2021-06-23, 最終更新日: 2023-10-25)

主引用文献

Kneller, D.W.,Li, H.,Galanie, S.,Phillips, G.,Labbe, A.,Weiss, K.L.,Zhang, Q.,Arnould, M.A.,Clyde, A.,Ma, H.,Ramanathan, A.,Jonsson, C.B.,Head, M.S.,Coates, L.,Louis, J.M.,Bonnesen, P.V.,Kovalevsky, A.
Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease.
J.Med.Chem., 64:17366-17383, 2021

PubMed Abstract: Creating small-molecule antivirals specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is crucial to battle coronavirus disease 2019 (COVID-19). SARS-CoV-2 main protease (M) is an established drug target for the design of protease inhibitors. We performed a structure-activity relationship (SAR) study of noncovalent compounds that bind in the enzyme's substrate-binding subsites S1 and S2, revealing structural, electronic, and electrostatic determinants of these sites. The study was guided by the X-ray/neutron structure of M complexed with Mcule-5948770040 (compound ), in which protonation states were directly visualized. Virtual reality-assisted structure analysis and small-molecule building were employed to generate analogues of . enzyme inhibition assays and room-temperature X-ray structures demonstrated the effect of chemical modifications on M inhibition, showing that (1) maintaining correct geometry of an inhibitor's P1 group is essential to preserve the hydrogen bond with the protonated His163; (2) a positively charged linker is preferred; and (3) subsite S2 prefers nonbulky modestly electronegative groups.

PubMed: 34705466
DOI: 10.1021/acs.jmedchem.1c01475

実験手法

NEUTRON DIFFRACTION (2.5 Å)
X-RAY DIFFRACTION (2.2 Å)