Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS‐CoV‐2 Spike Protein

Shoemark, Deborah K.; Colenso, Charlotte K.; Toelzer, Christine; Gupta, Kapil; Sessions, Richard B.; Davidson, Andrew D.; Berger, Imre; Schaffitzel, Christiane; Spencer, James; Mulholland, Adrian J.

We investigate binding of linoleate and other potential ligands to the recently discovered fatty acid binding site in the SARS‐CoV‐2 spike protein, using docking and molecular dynamics simulations. Simulations suggest that linoleate and dexamethasone stabilize the locked spike conformation, thus reducing the opportunity for ACE2 interaction. In contrast, cholesterol may expose the receptor‐binding domain by destabilizing the closed structure, preferentially binding to a different site in the hinge region of the open structure. We docked a library of FDA‐approved drugs to the fatty acid site using an approach that reproduces the structure of the linoleate complex. Docking identifies steroids (including dexamethasone and vitamin D); retinoids (some known to be active in vitro, and vitamin A); and vitamin K as potential ligands that may stabilize the closed conformation. The SARS‐CoV‐2 spike fatty acid site may bind a diverse array of ligands, including dietary components, and therefore provides a promising target for therapeutics or prophylaxis.