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

preprint
submitted on 03.06.2020 and posted on 04.06.2020 by zheng zhao, Phil bourne
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.

Funding

the University of Virginia

History

Email Address of Submitting Author

zz7r@virginia.edu

Institution

School of Data Science and Department of Biomedical Engineering, University of Virginia

Country

United States of America

ORCID For Submitting Author

0000-0003-1453-3230

Declaration of Conflict of Interest

no conflict of interest

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