Identification and Investigation of a Cryptic Binding Pocket of the P37 Envelope Protein of Monkeypox Virus by Molecular Dynamics Simulations.
J Phys Chem Lett
; 14(13): 3230-3235, 2023 Apr 06.
Article
in English
| MEDLINE | ID: covidwho-2280490
ABSTRACT
The spread of the monkeypox virus has surged during the unchecked COVID-19 epidemic. The most crucial target is the viral envelope protein, p37. However, lacking p37's crystal structure is a significant hurdle to rapid therapeutic discovery and mechanism elucidation. Structural modeling and molecular dynamics (MD) of the enzyme with inhibitors reveal a cryptic pocket occluded in the unbound structure. For the first time, the inhibitor's dynamic flip from the active to the cryptic site enlightens p37's allosteric site, which squeezes the active site, impairing its function. A large force is needed for inhibitor dissociation from the allosteric site, ushering in its biological importance. In addition, hot spot residues identified at both locations and discovered drugs more potent than tecovirimat may enable even more robust inhibitor designs against p37 and accelerate the development of monkeypox therapies.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Molecular Dynamics Simulation
/
COVID-19
Type of study:
Diagnostic study
Limits:
Humans
Language:
English
Journal:
J Phys Chem Lett
Year:
2023
Document Type:
Article
Affiliation country:
Acs.jpclett.3c00087
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