Structural Insights into the Binding Modes of Viral RNA-Dependent RNA Polymerases Using a Function-Site Interaction Fingerprint Method for RNA Virus Drug Discovery.
J Proteome Res
; 19(11): 4698-4705, 2020 11 06.
Article
in English
| MEDLINE | ID: covidwho-960286
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
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This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
See preprint
ABSTRACT
The coronavirus disease of 2019 (COVID-19) pandemic speaks to the need for drugs that not only are effective but also remain effective given the mutation rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To this end, we describe structural binding-site insights for facilitating COVID-19 drug design when targeting RNA-dependent RNA polymerase (RDRP), a common conserved component of RNA viruses. We combined an RDRP structure data set, including 384 RDRP PDB structures and all corresponding RDRP-ligand interaction fingerprints, thereby revealing the structural characteristics of the active sites for application to RDRP-targeted drug discovery. Specifically, we revealed the intrinsic ligand-binding modes and associated RDRP structural characteristics. Four types of binding modes with corresponding binding pockets were determined, suggesting two major subpockets available for drug discovery. We screened a drug data set of 7894 compounds against these binding pockets and presented the top-10 small molecules as a starting point in further exploring the prevention of virus replication. In summary, the binding characteristics determined here help rationalize RDRP-targeted drug discovery and provide insights into the specific binding mechanisms important for containing the SARS-CoV-2 virus.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Pneumonia, Viral
/
Viral Proteins
/
RNA-Dependent RNA Polymerase
/
Coronavirus Infections
/
Drug Discovery
/
Betacoronavirus
Limits:
Humans
Language:
English
Journal:
J Proteome Res
Journal subject:
Biochemistry
Year:
2020
Document Type:
Article
Affiliation country:
Acs.jproteome.0c00623
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