An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase
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 tre...
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sg-ntu-dr.10356-1758362024-05-08T00:56:46Z An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase Zhang, Yunju Guo, Jingjing Liu, Yang Qu, Yuanyuan Li, Yong-Qiang Mu, Yuguang Li, Weifeng School of Biological Sciences Medicine, Health and Life Sciences SARS-CoV-2 main proteinase Allosteric inhibitor 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. This work is supported by the Natural Science Foundation of Shandong Province (ZR2020JQ04) and the Local Science and Technology Development Fund Guided by the Central Government of Shandong Province (YDZX2022089). The authors sincerely thank the support from Core Facility Sharing Platform of Shandong University and National Demonstration Center for Experimental Physics Education (Shandong University). 2024-05-08T00:56:46Z 2024-05-08T00:56:46Z 2024 Journal Article 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 0141-8130 https://hdl.handle.net/10356/175836 10.1016/j.ijbiomac.2024.130644 38462102 2-s2.0-85187957078 Pt 1 265 130644 en International Journal of Biological Macromolecules © 2024 Elsevier B.V. All rights reserved. |
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Medicine, Health and Life Sciences SARS-CoV-2 main proteinase Allosteric inhibitor Zhang, Yunju Guo, Jingjing Liu, Yang Qu, Yuanyuan Li, Yong-Qiang Mu, Yuguang Li, Weifeng An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase |
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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. |
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School of Biological Sciences |
author_facet |
School of Biological Sciences Zhang, Yunju Guo, Jingjing Liu, Yang Qu, Yuanyuan Li, Yong-Qiang Mu, Yuguang Li, Weifeng |
format |
Article |
author |
Zhang, Yunju Guo, Jingjing Liu, Yang Qu, Yuanyuan Li, Yong-Qiang Mu, Yuguang Li, Weifeng |
author_sort |
Zhang, Yunju |
title |
An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase |
title_short |
An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase |
title_full |
An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase |
title_fullStr |
An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase |
title_full_unstemmed |
An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase |
title_sort |
allosteric mechanism for potent inhibition of sars-cov-2 main proteinase |
publishDate |
2024 |
url |
https://hdl.handle.net/10356/175836 |
_version_ |
1800916205987430400 |