TY - JOUR
T1 - An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase
AU - Zhang, Yunju
AU - Guo, Jingjing
AU - Liu, Yang
AU - Qu, Yuanyuan
AU - Li, Yong Qiang
AU - Mu, Yuguang
AU - Li, Weifeng
N1 - Publisher Copyright:
© 2024 Elsevier B.V.
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - Allosteric inhibitor
KW - Dynamical network
KW - MM-GBSA
KW - Molecular dynamic simulation
KW - SARS-CoV-2 main proteinase
UR - http://www.scopus.com/inward/record.url?scp=85187957078&partnerID=8YFLogxK
U2 - 10.1016/j.ijbiomac.2024.130644
DO - 10.1016/j.ijbiomac.2024.130644
M3 - Article
C2 - 38462102
AN - SCOPUS:85187957078
SN - 0141-8130
VL - 265
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
M1 - 130644
ER -