Cho, E;
Rosa, M;
Anjum, R;
Mehmood, S;
Soban, M;
Mujtaba, M;
Bux, K;
... Haider, S; + view all
(2021)
Dynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites.
Journal of Chemical Information and Modeling
, 61
(6)
pp. 3058-3073.
10.1021/acs.jcim.1c00449.
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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.
| Type: | Article |
|---|---|
| Title: | Dynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.jcim.1c00449 |
| Publisher version: | http://dx.doi.org/10.1021/acs.jcim.1c00449 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Antiviral Agents, Binding Sites, COVID-19, Humans, Ligands, Peptide Hydrolases, Protease Inhibitors, RNA, Viral, SARS-CoV-2 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10130639 |
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