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Synergistic Inhibitor Binding to the Papain‐Like Protease of Human SARS Coronavirus: Mechanistic and Inhibitor Design Implications
Author(s) -
Lee Hyun,
Cao Shuyi,
Hevener Kirk E.,
Truong Lena,
Gatuz Joseph L.,
Patel Kavankumar,
Ghosh Arun K.,
Johnson Michael E.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300134
Subject(s) - papain , chemistry , protease , enzyme , surface plasmon resonance , docking (animal) , lead compound , drug discovery , biochemistry , coronavirus , binding site , combinatorial chemistry , covid-19 , protease inhibitor (pharmacology) , stereochemistry , active site , proteases , biology , in vitro , virus , virology , nanotechnology , nanoparticle , viral load , medicine , materials science , nursing , disease , pathology , antiretroviral therapy , infectious disease (medical specialty)
Abstract We previously developed two potent chemical classes that inhibit the essential papain‐like protease (PLpro) of severe acute respiratory syndrome coronavirus. In this study, we applied a novel approach to identify small fragments that act synergistically with these inhibitors. A fragment library was screened in combination with four previously developed lead inhibitors by fluorescence‐based enzymatic assays. Several fragment compounds synergistically enhanced the inhibitory activity of the lead inhibitors by approximately an order of magnitude. Surface plasmon resonance measurements showed that three fragments bind specifically to the PLpro enzyme. Mode of inhibition, computational solvent mapping, and molecular docking studies suggest that these fragments bind adjacent to the binding site of the lead inhibitors and further stabilize the inhibitor‐bound state. We propose potential next‐generation compounds based on a computational fragment‐merging approach. This approach provides an alternative strategy for lead optimization for cases in which direct co‐crystallization is difficult.