<p>Following our recent
identification of a fatty acid binding site in the SARS-CoV-2 spike protein (Toelzer
<i>et al., Science</i> eabd3255 (2020)), we investigate the binding of linoleate
and other potential ligands at this site using molecular dynamics simulations.
The results support the hypothesis that linoleate stabilises the locked form of
the spike, in which its interaction interface for the ACE2 receptor is occluded.
The simulations indicate weaker binding of linoleate to the partially open
conformation. Simulations of dexamethasone bound at this site indicate that it
binds similarly to linoleate, and thus may also stabilize a locked spike
conformation. In contrast, simulations suggest that cholesterol bound at this
site may destabilize the locked conformation, and in the open conformation, may
preferentially bind at an alternative site in the hinge region between the receptor
binding domain and the domain below, which could have functional relevance. We
also use molecular docking to identify potential ligands that may bind at the
fatty acid binding site, using the Bristol University Docking Engine (BUDE).
BUDE docking successfully reproduces the linoleate complex and also supports
binding of dexamethasone at the spike fatty acid site. Virtual screening of a
library of approved drugs identifies vitamins D, K and A, as well as retinoid
ligands with experimentally demonstrated activity against SARS-CoV-2 replication
<i>in vitro</i>, as also potentially able to bind at this site. Our data
suggest that the fatty acid binding site of the SARS-CoV-2 spike protein may
bind a diverse array of candidate ligands. Targeting this site with small
molecules, including dietary components such as vitamins, which may stabilise its
locked conformation and represents a potential avenue for novel therapeutics or
prophylaxis for COVID-19.</p>