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ORIGINAL RESEARCH article
Front. Mol. Biosci.
Sec. Biological Modeling and Simulation
Volume 11 - 2024 |
doi: 10.3389/fmolb.2024.1451280
A Potential Allosteric Inhibitor of SARS-CoV-2 Main Protease (M pro ) Identified through Metastable State Analysis
Provisionally accepted- Hamad bin Khalifa University, Doha, Qatar
Anti-COVID19 drugs, such as nirmatrelvir, have been developed targeting the SARS-CoV-2 main protease, M pro , based on the critical requirement of its proteolytic processing of the viral polyproteins into functional proteins essential for viral replication. However, the emergence of SARS-CoV-2 variants with M pro mutations has raised the possibility of developing resistance against these drugs, likely due to therapeutic targeting of the M pro catalytic site. An alternative to these drugs is the development of drugs that target an allosteric site distant from the catalytic site in the protein that may reduce the chance of the emergence of resistant mutants. Here, we combine computational analysis with in vitro assay and report the discovery of a potential allosteric site and an allosteric inhibitor of SARS-CoV-2 M pro . Specifically, we identified a M pro metastable state with a deformed catalytic site harboring potential allosteric sites, raising the possibility that stabilization of this metastable state through a ligand binding can lead to inhibition of M pro activity. We then performed a computational screening of a library (~4.2 million) of drug-like compounds from the ZINC database and identified several candidate molecules with high predicted binding affinity. MD simulations showed stable binding of the three top-ranking compounds to the putative allosteric sites in the protein. Finally, we tested the three compounds in vitro using a BRET-based M pro biosensor and found one of the compounds (ZINC4497834) to inhibit M pro activity. We envisage that the identification of a potential allosteric inhibitor of M pro will aid in developing improved anti-COVID-19 therapy.
Keywords: COVID-19, MD simulation, Metastable states, M Pro, Zinc15
Received: 18 Jun 2024; Accepted: 14 Aug 2024.
Copyright: © 2024 Fatima, M Geethakumari, Ahmed, PhD and Biswas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Kabir H. Biswas, Hamad bin Khalifa University, Doha, Qatar
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