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.S imulations suggest that linoleate and dexamethasone stabilizet he locked spike conformation, thus reducing the opportunity for ACE2 interaction. In contrast, cholesterol may expose the receptor-binding domain by destabilizing the closed structure,p referentially binding to ad ifferent site in the hinge region of the open structure.W ed ocked al ibrary 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);r etinoids (some knownt ob e active in vitro,a nd vitamin A);a nd vitamin Ka sp otential ligands that may stabilizethe closed conformation. The SARS-CoV-2 spike fatty acid site may bind adiverse arrayofligands, including dietary components,and therefore provides apromising target for therapeutics or prophylaxis.

Could isotretinoin be a protective agent against COVID‐19?: A dermatologist perspective

“…ISO was identified, among other retinoids, to inhibit SARS-CoV-2 replication in Vero E6 cells. Shoemark et al 1 noted that ISO may bind to the SARS-CoV-2 spike protein at SARS-CoV-2 spike fatty acid site, influencing the conformational changes required for receptor binding, stabilizing the locked ACE2 conformation of the spike protein. That reduces the opportunity for receptor-mediated cell entry via interaction with ACE2.…”

“…In this way, isotretinoin may affect viral entry, particularly in the early stage of the infection process. 1 Moreover, ISO upregulates the host antiviral response, through stimulation of interferon-1 (IFN-I) secretion, potentiating immune response to it, and eventually reduces viral infectivity. 1 Spike protein interaction is limited not only to ACE2, but also to neuropilin receptors (NRPs) in cells where ACE2 expression is low.…”

“…1 Moreover, ISO upregulates the host antiviral response, through stimulation of interferon-1 (IFN-I) secretion, potentiating immune response to it, and eventually reduces viral infectivity. 1 Spike protein interaction is limited not only to ACE2, but also to neuropilin receptors (NRPs) in cells where ACE2 expression is low. Notably, NRPs are highly expressed in human lung tissue and olfactory epithelium compared to ACE2.…”

SARS-CoV-2 Spike Protein Mutations and Escape from Antibodies: a Computational Model of Epitope Loss in Variants of Concern

“…In this work, we analyzed full-length models of 7 trimeric glycosylated SARS-CoV-2 S protein variants, derived from the prefusion conformation of the cryo-EM structure 6VSB [3a] , in which the Receptor Binding Domain of chain A (RBD-A) is in an "up" conformation, exposed to interaction with host cell receptors and potential targeting by Abs. The data from our energetic analyses can be aptly integrated in the characterization of the properties of S and other SARS-CoV-2 proteins from long scale simulations, such as those recently presented by Zimmerman et al coworkers [18] , Casalino et al [17e] , Spinello et al [19] , Oliveira et al [20] , Shoemark et al [21] , and Wang et al [22] .…”

Immunopathogenesis of Different Emerging Viral Infections: Evasion, Fatal Mechanism, and Prevention

“…For instance, maintenance of host interior homeostasis on vitamins (e.g. vitamin D, retinoids, vitamin K2) and metabolites of microbiota, which provide anti-virus properties and/or better Treg responses for anti-inflammatory reactions (179)(180)(181)(182)(183)(184), may regulate immunity and reduce mortality of an emerging infection.…”