Open AccessStructural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease
Author(s) -
Daniel W. Kneller,
Hui Li,
Stephanie Galanie,
G.N. Phillips,
Audrey Labbé,
Kevin L. Weiss,
Qiu Zhang,
Mark A. Arnould,
Austin Clyde,
Huadóng Ma,
Arvind Ramanathan,
Colleen B. Jonsson,
Martha S. Head,
Leighton Coates,
John M. Louis,
Peter V. Bonnesen,
Andrey Kovalevsky
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c01475
Subject(s) - chemistry , protease , protonation , stereochemistry , enzyme inhibitor , hydrogen bond , enzyme , active site , small molecule , molecule , substrate (aquarium) , covid-19 , coronavirus , linker , binding site , structure–activity relationship , protease inhibitor (pharmacology) , in vitro , biochemistry , virology , virus , organic chemistry , antiretroviral therapy , pathology , computer science , viral load , biology , operating system , medicine , disease , infectious disease (medical specialty) , geology , ion , oceanography
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 pro ) 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 pro complexed with Mcule-5948770040 (compound 1 ), in which protonation states were directly visualized. Virtual reality-assisted structure analysis and small-molecule building were employed to generate analogues of 1 . In vitro enzyme inhibition assays and room-temperature X-ray structures demonstrated the effect of chemical modifications on M pro 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.