Structural insights into the binding modes of viral RNA-dependent RNA polymerases using a function-site interaction fingerprint method for RNA virus drug discovery

Zheng Zhao, Phil Bourne

10.26434/chemrxiv.12413360.v1

Research curated

Abstract

The COVID-19 pandemic speaks to the need for drugs that are not only effective but also remain so given the mutation rate of COVID-19. To this end, we describe a strategy to design potential drugs that target RNA-dependent RNA polymerase (RDRP), a common conserved component of RNA viruses. We combine an RDRP structure dataset and all RDRP-ligand interaction fingerprints into an RDRP-targeted drug discovery procedure. In so doing we reveal the ligand-binding modes and RDRP structural characteristics. Specifically, four types of binding modes with corresponding binding pockets were determined, suggesting two major potential sub-pockets available for drug discovery. We screened a drug dataset of approximately 8,000 compounds against these binding pockets and presented the top ten 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.

Source: ChemRxiv

Related molecules

Name	Synonyms	Genes
Darexaban
Fimepinostat	CUDC-907
LY-517717
RNA dependent RNA polymerase	RDR, viral RNA polymerase, RdRp, nsp12	rep, ORF1a-1b, RdRp
4SC-202	Domatinostat (tosylate)
N-({(2S)-1-[(3R)-3-AMINO-4-(2-FLUOROPHENYL)BUTANOYL]PYRROLIDIN-2-YL}METHYL)BENZAMIDE	DB07779
D-phenylalanyl-N-{4-[amino(iminio)methyl]benzyl}-L-prolinamide	DB07005
6-CARBAMIMIDOYL-4-(3-HYDROXY-2-METHYL-BENZOYLAMINO)-NAPHTHALENE-2-CARBOXYLIC ACID METHYL ESTER	DB07074
Osimertinib
Pentamidine
Nafamostat	Nafamostat mesylate, p-Guanidinobenzoic acid ester with 6-hydroxy-2-naphthamidine

Related interactions

Target	Drug	Type	Result
RNA dependent RNA polymerase	Darexaban	Computational	positive
RNA dependent RNA polymerase	4SC-202	Computational	positive
RNA dependent RNA polymerase	N-({(2S)-1-[(3R)-3-AMINO-4-(2-FLUOROPHENYL)BUTANOYL]PYRROLIDIN-2-YL}METHYL)BENZAMIDE	Computational	positive
RNA dependent RNA polymerase	Osimertinib	Computational	positive
RNA dependent RNA polymerase	Fimepinostat	Computational	positive
RNA dependent RNA polymerase	D-phenylalanyl-N-{4-[amino(iminio)methyl]benzyl}-L-prolinamide	Computational	positive
RNA dependent RNA polymerase	LY-517717	Computational	positive
RNA dependent RNA polymerase	Pentamidine	Computational	positive
RNA dependent RNA polymerase	6-CARBAMIMIDOYL-4-(3-HYDROXY-2-METHYL-BENZOYLAMINO)-NAPHTHALENE-2-CARBOXYLIC ACID METHYL ESTER	Computational	positive
RNA dependent RNA polymerase	Nafamostat	Computational	positive