Structure-Based in Silico Screening Identifies a Potent Ebolavirus Inhibitor from a Traditional Chinese Medicine Library

Potent Ebolavirus (EBOV) inhibitors
will help to curtail outbreaks
such as that which occurred in 2014–16 in West Africa. EBOV
has on its surface a single glycoprotein (GP) critical for viral entry
and membrane fusion. Recent high-resolution complexes of EBOV GP with
a variety of approved drugs revealed that binding to a common cavity
prevented fusion of the virus and endosomal membranes, inhibiting
virus infection. We performed docking experiments, screening a database
of natural compounds to identify those likely to bind at this site.
Using both inhibition assays of HIV-1-derived pseudovirus cell entry
and structural analyses of the complexes of the compounds with GP,
we show here that two of these compounds attach in the common binding
cavity, out of eight tested. In both cases, two molecules bind in
the cavity. The two compounds are chemically similar, but the tighter
binder has an additional chlorine atom that forms good halogen bonds
to the protein and achieves an IC50 of 50 nM, making it
the most potent GP-binding EBOV inhibitor yet identified, validating
our screening approach for the discovery of novel antiviral compounds.