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Title: | Dynamic Profiling of β-Coronavirus 3CL M<sup>pro</sup>Protease Ligand-Binding Sites |
Authors: | Cho, E Rosa, M Anjum, R Mehmood, S Soban, M Mujtaba, M Bux, K Moin, ST Tanweer, M Dantu, S Pandini, A Yin, J Ma, H Ramanathan, A Islam, B Mey, ASJS Bhowmik, D Haider, S |
Issue Date: | 14-Jun-2021 |
Publisher: | ACS Publications |
Citation: | Cho, E. et al. (2021) 'Dynamic Profiling of β-Coronavirus 3CL M<sup>pro</sup>Protease Ligand-Binding Sites', Journal of Chemical Information and Modeling, 2021, 61 (6), pp. 3058 - 3073. doi: 10.1021/acs.jcim.1c00449. |
Abstract: | β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand–protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor. |
Description: | Data availability statement: The trajectories of Mpro simulations and models of the metastable states can be downloaded from 10.5281/zenodo.4782284. |
URI: | https://bura.brunel.ac.uk/handle/2438/26711 |
DOI: | https://doi.org/10.1021/acs.jcim.1c00449 |
ISSN: | 1549-9596 |
Other Identifiers: | ORCID iDs: Syed T. Moin https://orcid.org/0000-0002-2868-7663; Sarath Dantu https://orcid.org/0000-0003-2019-5311; Alessandro Pandini https://orcid.org/0000-0002-4158-233X; Barira Islam https://orcid.org/0000-0001-5882-6903; Antonia S. J. S. Mey https://orcid.org/0000-0001-7512-5252; Debsindhu Bhowmik https://orcid.org/0000-0002-2868-7663; Shozeb Haider https://orcid.org/0000-0003-2650-2925. |
Appears in Collections: | Dept of Computer Science Research Papers |
Files in This Item:
File | Description | Size | Format | |
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FullText.pdf | This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © 2021 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see ACS Articles on Request at https://pubs.acs.org/page/4authors/benefits/index.html#articles-request and https://pubs.acs.org/page/copyright/journals/posting_policies.html. | 21.77 MB | Adobe PDF | View/Open |
Appendix_Table-S1-S6.pdf | This document includes the tables accompanying the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © 2021 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see ACS Articles on Request at https://pubs.acs.org/page/4authors/benefits/index.html#articles-request and https://pubs.acs.org/page/copyright/journals/posting_policies.html. | 106.22 kB | Adobe PDF | View/Open |
Supporting-Information.pdf | This document includes the supporting information accompanying the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © 2021 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see ACS Articles on Request at https://pubs.acs.org/page/4authors/benefits/index.html#articles-request and https://pubs.acs.org/page/copyright/journals/posting_policies.html. | 24.71 MB | Adobe PDF | View/Open |
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