Structural Insights into the Binding Modes of Viral RNA-Dependent RNA Polymerases Using a Function-Site Interaction Fingerprint Method for RNA Virus Drug Discovery

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.