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

Abstract

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.

Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein

“…Rational drug design approaches have been directed toward the LA pocket with the aim of stabilizing receptor binding-incompetent closed conformations (Ellis et al, 2021; -S3. Shoemark et al, 2021). It appears that the LA pocket also has long-range effects on allosteric networks that include neighboring chains, NTD, and distant S1/S2 cleavage sites (Oliveira et al, 2022;Tan et al, 2022).…”

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

“…Another hormone in Table 1 is calcitriol (1,25-dihydroxycholecalciferol vitamin D), a steroid hormone that binds to and activates the vitamin D receptor in the nucleus of the cell, regulating multiple genes. Other groups have identified calcitriol and other steroids as ligands for the S protein FABP [ 6 , 32 ]. Unlike other steroids, calcitriol interacts with Arg408 and Gln409 on S, which increases its binding affinity.…”

“…It also had an EC 50 value of 9.6 µM in Vero E6 cells, which was attributed to binding to the spike RBD [ 37 ]. Shoemark and colleagues also reported Vitamin K2 as a best binder, and adapalene and vitamin A as a tight binders to the FABP [ 6 ]. Figure 4 shows a superimposition of linoleic acid with adapalene in the spike FABP.…”

“…For example, Shoemark et al reported a docking and molecular dynamics (MD) study of binding of LA and other ligands to the FABP. This suggested linoleate and dexamethasone stabilized the locked S conformation, while cholesterol destabilized it by binding to another site in the hinge region [ 6 ]. Another study of eight putative binding sites on the S protein identified additional ligands that bind to the FABP and stabilize the closed conformation [ 7 ].…”

The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach

“…Two forms of spike trimer have been reported in previous studies: open (Apo) and Locked S conformer. Recent findings indicated that switching Apo to Locked form could significantly reduce the spike protein affinity to ACE2 though the interaction of ligands to fatty acid binding pocket (FAB) of spike trimer 34,35 . Protease is an essential enzyme present in viruses 36 .…”