7N8C

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

Summary for 7N8C

• Entry DOI: 10.2210/pdb7n8c/pdb
• Descriptor: 3C-like proteinase, 6-[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl-1~{H}-pyrimidine-2,4-dione (3 entities in total)
• Functional Keywords: cysteine protease, inhibitor complex, protonation states, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34194.75

Authors

Kovalevsky, A.,Kneller, D.W.,Coates, L. (deposition date: 2021-06-14, release date: 2021-06-23, Last modification date: 2023-10-25)

Primary citation

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

Experimental method

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