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Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling

journal contribution
posted on 06.05.2022, 17:19 by Hyun LeeHyun Lee, Jinhong Ren, Russell PesaventoRussell Pesavento, Isabel Ojeda, Amy J Rice, Haining Lv, Youngjin Kwon, Michael JohnsonMichael Johnson
The development of new therapeutic agents against the coronavirus causing Middle East Respiratory Syndrome (MERS) is a continuing imperative. The initial MERS-CoV epidemic was contained entirely through public health measures, but episodic cases continue, as there are currently no therapeutic agents effective in the treatment of MERS-CoV, although multiple strategies have been proposed. In this study, we screened 30,000 compounds from three different compound libraries against one of the essential proteases, the papain-like protease (PLpro), using a fluorescence-based enzymatic assay followed by surface plasmon resonance (SPR) direct binding analysis for hit confirmation. Mode of inhibition assays and competition SPR studies revealed two compounds to be competitive inhibitors. To improve upon the inhibitory activity of the best hit compounds, a small fragment library consisting of 352 fragments was screened in the presence of each hit compound, resulting in one fragment that enhanced the IC50 value of the best hit compound by 3-fold. Molecular docking and MM/PBSA binding energy calculations were used to predict potential binding sites, providing insight for design and synthesis of next-generation compounds.

Funding

Development of PLpro and 3CLpro Protease Inhibitors as Novel SARS Therapeutics | Funder: National Institutes of Health (National Institute of Allergy and Infectious Diseases) | Grant ID: R56AI089535

History

Citation

Lee, H., Ren, J., Pesavento, R. P., Ojeda, I., Rice, A. J., Lv, H., Kwon, Y.Johnson, M. E. (2019). Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling. Bioorganic & Medicinal Chemistry, 27(10), 1981-1989. https://doi.org/10.1016/j.bmc.2019.03.050

Publisher

Elsevier BV

Language

en

issn

0968-0896