Modeling the Structure-Activity Relationship of Arbidol Derivatives and Other SARS-CoV-2 Fusion Inhibitors Targeting the S2 Segment of the Spike Protein.
J Chem Inf Model
; 61(12): 5906-5922, 2021 12 27.
Article
in English
| MEDLINE | ID: covidwho-1569200
ABSTRACT
Umifenovir (Arbidol) has been reported to exhibit some degree of efficacy in multiple clinical trials for the treatment of COVID-19 as a monotherapy. It has also demonstrated synergistic inhibition of SARS-CoV-2 with other direct-acting antivirals such as Remdesivir. A computational approach was used to identify the most favorable binding site to the SARS-CoV-2 Spike S2 segment and to perform virtual screening. Compounds selected from modeling were evaluated in a live SARS-CoV-2 infection assay. An Arbidol (ARB) derivative with substitutions at both the C-4 and C-6 positions was found to exhibit a modest improvement in activity and solubility properties in comparison to ARB. However, all of the derivatives were found to only be partial inhibitors, rather than full inhibitors in a virus-induced cytopathic effect-based assay. The binding mode is also corroborated by parallel modeling of a series of oleanolic acid trisaccharide saponin fusion inhibitors shown to bind to the S2 segment. Recently determined experimental structures of the Spike protein allowed atomic resolution modeling of fusion inhibitor binding as a function of pH, and the implications for the molecular mechanism of direct-acting fusion inhibitors targeting the S2 segment are discussed.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Hepatitis C, Chronic
/
COVID-19
Type of study:
Experimental Studies
/
Prognostic study
Limits:
Humans
Language:
English
Journal:
J Chem Inf Model
Journal subject:
Medical Informatics
/
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
Acs.jcim.1c01061
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