Open AccessDynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites
Author(s) -
Eunice Cho,
Margarida Rosa,
Rubi Anjum,
Saman Mehmood,
Mariya Soban,
Moniza Mujtaba,
Khair Bux,
Syed Tarique Moin,
Mohammad Tanweer,
Sarath Chandra Dantu,
Alessandro Pandini,
Junqi Yin,
Huadóng Ma,
Arvind Ramanathan,
Barira Islam,
Antonia S. J. S. Mey,
Debsindhu Bhowmik,
Shozeb Haider
Publication year - 2021
Publication title -
journal of chemical information and modeling
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 160
eISSN - 1549-960X
pISSN - 1549-9596
DOI - 10.1021/acs.jcim.1c00449
Subject(s) - computational biology , coronavirus , binding site , ligand (biochemistry) , in silico , biology , chemistry , covid-19 , genetics , medicine , infectious disease (medical specialty) , gene , receptor , disease , pathology
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 (M pro ) that plays an indispensable role in viral replication. The availability of over 270 M pro 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 M pro . 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 M pro enzymes with a single pan inhibitor.