Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/175836
Title: An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase
Authors: Zhang, Yunju
Guo, Jingjing
Liu, Yang
Qu, Yuanyuan
Li, Yong-Qiang
Mu, Yuguang
Li, Weifeng
Keywords: Medicine, Health and Life Sciences
Issue Date: 2024
Source: Zhang, Y., Guo, J., Liu, Y., Qu, Y., Li, Y., Mu, Y. & Li, W. (2024). An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase. International Journal of Biological Macromolecules, 265(Pt 1), 130644-. https://dx.doi.org/10.1016/j.ijbiomac.2024.130644
Journal: International Journal of Biological Macromolecules 
Abstract: The main proteinase (Mpro) of SARS-CoV-2 plays a critical role in cleaving viral polyproteins into functional proteins required for viral replication and assembly, making it a prime drug target for COVID-19. It is well known that noncompetitive inhibition offers potential therapeutic options for treating COVID-19, which can effectively reduce the likelihood of cross-reactivity with other proteins and increase the selectivity of the drug. Therefore, the discovery of allosteric sites of Mpro has both scientific and practical significance. In this study, we explored the binding characteristics and inhibiting process of Mpro activity by two recently reported allosteric inhibitors, pelitinib and AT7519 which were obtained by the X-ray screening experiments, to probe the allosteric mechanism via molecular dynamic (MD) simulations. We found that pelitinib and AT7519 can stably bind to Mpro far from the active site. The binding affinity is estimated to be -24.37 ± 4.14 and - 26.96 ± 4.05 kcal/mol for pelitinib and AT7519, respectively, which is considerably stable compared with orthosteric drugs. Furthermore, the strong binding caused clear changes in the catalytic site of Mpro, thus decreasing the substrate accessibility. The community network analysis also validated that pelitinib and AT7519 strengthened intra- and inter-domain communication of Mpro dimer, resulting in a rigid Mpro, which could negatively impact substrate binding. In summary, our findings provide the detailed working mechanism for the two experimentally observed allosteric sites of Mpro. These allosteric sites greatly enhance the 'druggability' of Mpro and represent attractive targets for the development of new Mpro inhibitors.
URI: https://hdl.handle.net/10356/175836
ISSN: 0141-8130
DOI: 10.1016/j.ijbiomac.2024.130644
Schools: School of Biological Sciences 
Rights: © 2024 Elsevier B.V. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SBS Journal Articles

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