Open AccessStructure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease
Author(s) -
Chamandi S. Dampalla,
Yun-Jeong Kim,
Naemi Bickmeier,
Athri D. Rathnayake,
Harry Nhat Nguyen,
Jian Zheng,
M.M. Kashipathy,
M.A. Baird,
Kevin P. Battaile,
Scott Lovell,
Stanley Perlman,
KyeongOk Chang,
William C. Groutas
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.1c00319
Subject(s) - chemistry , aldehyde , moiety , protease , stereochemistry , coronavirus , druggability , cocrystal , combinatorial chemistry , enzyme , biochemistry , covid-19 , molecule , hydrogen bond , organic chemistry , medicine , catalysis , disease , infectious disease (medical specialty) , gene
A series of nondeuterated and deuterated dipeptidyl aldehyde and masked aldehyde inhibitors that incorporate in their structure a conformationally constrained cyclohexane moiety was synthesized and found to potently inhibit severe acute respiratory syndrome coronavirus-2 3CL protease in biochemical and cell-based assays. Several of the inhibitors were also found to be nanomolar inhibitors of Middle East respiratory syndrome coronavirus 3CL protease. The corresponding latent aldehyde bisulfite adducts were found to be equipotent to the precursor aldehydes. High-resolution cocrystal structures confirmed the mechanism of action and illuminated the structural determinants involved in binding. The spatial disposition of the compounds disclosed herein provides an effective means of accessing new chemical space and optimizing pharmacological activity. The cellular permeability of the identified inhibitors and lack of cytotoxicity warrant their advancement as potential therapeutics for COVID-19.