Molecular mechanism of Ensitrelvir and its similarity inhibiting SARS-CoV-2 main protease by molecular dynamics simulation
Main Article Content
Abstract
The unprecedented challenge posed by the COVID-19 pandemic, driven by SARS-CoV-2, has emerged as a global threat. In response, a limited array of therapeutics has been approved for the prevention and treatment of SARS-CoV-2 infection. The main protease (Mpro) of SARS-CoV-2 has been a significant target for drug development efforts because of its crucial role in the viral replication process. This study is to investigate the efficacy of Ensitrelvir and its derivatives in inhibiting the mechanism of the Mpro target of SAR-CoV-2. Docking simulation and molecular dynamic simulation (SMD) techniques were employed for this purpose. The results indicate that the CID 166498740 derivative obtained affinity energy -9.3 kcal/mol and rupture force (Fmax) 638.3 ± 79.3 (pN), which proved that the CID 166498740 derivative strongly interacted with the Mpro target, emphasizing non-binding interactions as more crucial than hydrogen bonding in stabilizing the receptor-ligand conformation.
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Keywords
Derivatives of Ensitrelvir, docking method, Ensitrelvir, Mpro, SAR-CoV-2, SMD method
References
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Isralewitz, B., Gao, M., & Schulten, K. (2001). Steered molecular dynamics and mechanical functions of proteins. Current Opinion in Structural Biology, 11(2), 224-230.
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Sanner, M. F. (1999). Python: a programming language for software integration and development. Journal of Molecular Graphics and Modelling, 17(1), 57-61.
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Vuong, Q. V., Nguyen, T. T., & Li, M. S. (2015). A new method for navigating optimal direction for pulling ligand from binding pocket: application to ranking binding affinity by steered molecular dynamics. Journal of Chemical Information and Modeling, 55(12), 2731-2738.
Vuong, Q. V., Siposova, K., Nguyen, T. T., Antosova, A., Balogova, L., Drajna, L., Imrich, J., Li, M. S., & Gazova, Z. (2013). Binding of glyco-acridine derivatives to lysozyme leads to inhibition of amyloid fibrillization. Biomacromolecules, 14(4), 1035-1043.
Zhou, P., Yang, X.-L., Wang, X.-G., Hu, B., Zhang, L., Zhang, W., Si, H.-R., Zhu, Y., Li, B., Huang, C.-L., Chen, H.-D., Chen, J., Luo, Y., Guo, H., Jiang, R.-D., Liu, M.-Q., Chen, Y., Shen, X.-R., Wang, X., Zheng, X.-S., Zhao, K., Chen, Q.-J., Deng, F., Liu, L.-L., Yan, B., Zhan, F.-X., Wang, Y.-Y., Xiao, G.-F., & Shi, Z.-L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270-273. https://doi.org/10.1038/s41586-020-2012-7
Duan, Y., Zhou, H., Liu, X., Iketani, S., Lin, M., Zhang, X., Bian, Q., Wang, H., Sun, H., Hong, S. J., Culbertson, B., Mohri, H., Luck, M. I., Zhu, Y., Liu, X., Lu, Y., Yang, X., Yang, K., Sabo, Y., Chavez, A., Goff, S. P., Rao, Z., Ho, D. D., & Yang, H. (2023). Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir. Nature, 622(7982), 376-382. https://doi.org/10.1038/s41586-023-06609-0
Gorbalenya, A. E., Baker, S. C., Baric, R. S., de Groot, R. J., Drosten, C., Gulyaeva, A. A., Haagmans, B. L., Lauber, C., Leontovich, A. M., Neuman, B. W., Penzar, D., Perlman, S., Poon, L. L. M., Samborskiy, D. V., Sidorov, I. A., Sola, I., Ziebuhr, J., & Coronaviridae Study Group of the International Committee on Taxonomy of, V. (2020). The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nature Microbiology. https://doi.org/10.1038/s41564-020-0695-z
Grubmüller, H., Heymann, B., & Tavan, P. (1996). Ligand binding: molecular mechanics calculation of the streptavidin-biotin rupture force. Science, 271(5251), 997-999.
He, X., He, C., Hong, W., Yang, J., & Wei, X. (2023). Research progress in spike mutations of SARS‐CoV‐2 variants and vaccine development. Medicinal Research Reviews, 43(4), 932-971.
Isralewitz, B., Gao, M., & Schulten, K. (2001). Steered molecular dynamics and mechanical functions of proteins. Current Opinion in Structural Biology, 11(2), 224-230.
Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2022). PubChem 2023 update. Nucleic Acids Research, 51(D1), D1373-D1380. https://doi.org/10.1093/nar/gkac956
Kumar, S., & Li, M. S. (2010). Biomolecules under mechanical force. Physics Reports, 486(1), 1-74.
Lin, M., Zeng, X., Duan, Y., Yang, Z., Ma, Y., Yang, H., Yang, X., & Liu, X. (2023). Molecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants. Communications Biology, 6(1), 694.
Mondal, S., Chen, Y., Lockbaum, G. J., Sen, S., Chaudhuri, S., Reyes, A. C., Lee, J. M., Kaur, A. N., Sultana, N., & Cameron, M. D. (2022). Dual inhibitors of main protease (MPro) and Cathepsin L as potent antivirals against SARS-CoV2. Journal of the American Chemical Society, 144(46), 21035-21045.
Mukae, H., Yotsuyanagi, H., Ohmagari, N., Doi, Y., Imamura, T., Sonoyama, T., Fukuhara, T., Ichihashi, G., Sanaki, T., & Baba, K. (2022). A randomized phase 2/3 study of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection: results of the phase 2a part. Antimicrobial Agents and Chemotherapy, 66(10), e00697-00622.
Owen, D. R., Allerton, C. M., Anderson, A. S., Aschenbrenner, L., Avery, M., Berritt, S., Boras, B., Cardin, R. D., Carlo, A., & Coffman, K. J. (2021). An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science, 374(6575), 1586-1593.
Sanner, M. F. (1999). Python: a programming language for software integration and development. Journal of Molecular Graphics and Modelling, 17(1), 57-61.
Thai, N. Q., Nguyen, H. L., Linh, H. Q., & Li, M. S. (2017). Protocol for fast screening of multi-target drug candidates: Application to Alzheimer’s disease. Journal of Molecular Graphics and Modelling, 77, 121-129. https://doi.org/https://doi.org/10.1016/j.jmgm.2017.08.002
Thai, N. Q., Nguyen, N. Q., Nguyen, C., Nguyen, T. Q., Ho, K., Nguyen, T. T., & Li, M. S. (2018). Screening potential inhibitors for cancer target LSD1 from natural products by steered molecular dynamics. Molecular Simulation, 44(4), 335-342.
Trott, O., & Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455-461.
Unoh, Y., Uehara, S., Nakahara, K., Nobori, H., Yamatsu, Y., Yamamoto, S., Maruyama, Y., Taoda, Y., Kasamatsu, K., Suto, T., Kouki, K., Nakahashi, A., Kawashima, S., Sanaki, T., Toba, S., Uemura, K., Mizutare, T., Ando, S., Sasaki, M., Orba, Y., Sawa, H., Sato, A., Sato, T., Kato, T., & Tachibana, Y. (2022). Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19. Journal of Medicinal Chemistry, 65(9), 6499-6512. https://doi.org/10.1021/acs.jmedchem.2c00117
Vuong, Q. V., Nguyen, T. T., & Li, M. S. (2015). A new method for navigating optimal direction for pulling ligand from binding pocket: application to ranking binding affinity by steered molecular dynamics. Journal of Chemical Information and Modeling, 55(12), 2731-2738.
Vuong, Q. V., Siposova, K., Nguyen, T. T., Antosova, A., Balogova, L., Drajna, L., Imrich, J., Li, M. S., & Gazova, Z. (2013). Binding of glyco-acridine derivatives to lysozyme leads to inhibition of amyloid fibrillization. Biomacromolecules, 14(4), 1035-1043.
Zhou, P., Yang, X.-L., Wang, X.-G., Hu, B., Zhang, L., Zhang, W., Si, H.-R., Zhu, Y., Li, B., Huang, C.-L., Chen, H.-D., Chen, J., Luo, Y., Guo, H., Jiang, R.-D., Liu, M.-Q., Chen, Y., Shen, X.-R., Wang, X., Zheng, X.-S., Zhao, K., Chen, Q.-J., Deng, F., Liu, L.-L., Yan, B., Zhan, F.-X., Wang, Y.-Y., Xiao, G.-F., & Shi, Z.-L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270-273. https://doi.org/10.1038/s41586-020-2012-7
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