Journal
CHEMMEDCHEM
Volume 8, Issue 8, Pages 1361-1372Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201300134
Keywords
fragments; human SARS coronavirus; inhibitors; papain-like protease; small molecules
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Funding
- US National Institutes of Health (NIH) [R56 AI089535]
- National Science Foundation [OCI-1053575]
- US National Institute of Dental and Craniofacial Research (NIDCR), University of Illinois at Chicago College of Dentistry, MOST program [5T32-DE018381]
- US NIH [P41 RR001081]
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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.
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