Mechanistic investigation of SARS-CoV-2 main protease to accelerate design of covalent inhibitors.
Sci Rep
; 12(1): 21037, 2022 Dec 05.
Article
in English
| MEDLINE | ID: covidwho-2151084
ABSTRACT
Targeted covalent inhibition represents one possible strategy to block the function of SARS-CoV-2 Main Protease (MPRO), an enzyme that plays a critical role in the replication of the novel SARS-CoV-2. Toward the design of covalent inhibitors, we built a covalent inhibitor dataset using deep learning models followed by high throughput virtual screening of these candidates against MPRO. Two top-ranking inhibitors were selected for mechanistic investigations-one with an activated ester warhead that has a piperazine core and the other with an acrylamide warhead. Specifically, we performed a detailed analysis of the free energetics of covalent inhibition by hybrid quantum mechanics/molecular mechanics simulations. Cleavage of a fragment of the non-structured protein (NSP) from the SARS-CoV-2 genome was also simulated for reference. Simulations show that both candidates form more stable enzyme-inhibitor (E-I) complexes than the chosen NSP. It was found that both the NSP fragment and the activated ester inhibitor react with CYS145 of MPRO in a concerted manner, whereas the acrylamide inhibitor follows a stepwise mechanism. Most importantly, the reversible reaction and the subsequent hydrolysis reaction from E-I complexes are less probable when compared to the reactions with an NSP fragment, showing promise for these candidates to be the base for efficient MPRO inhibitors.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
SARS-CoV-2
/
COVID-19 Drug Treatment
Limits:
Humans
Language:
English
Journal:
Sci Rep
Year:
2022
Document Type:
Article
Affiliation country:
S41598-022-23570-6
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