Dynamic Profiling of ß-Coronavirus 3CL Mpro Protease Ligand-Binding Sites.
J Chem Inf Model
; 61(6): 3058-3073, 2021 06 28.
Article
in English
| MEDLINE | ID: covidwho-1313532
ABSTRACT
ß-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 ß-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Peptide Hydrolases
/
COVID-19
Topics:
Vaccines
/
Variants
Limits:
Humans
Language:
English
Journal:
J Chem Inf Model
Journal subject:
Medical Informatics
/
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
Acs.jcim.1c00449
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