In silico identification of strong binders of the SARS-CoV-2 receptor-binding domain

Abstract

The world is currently witnessing the spread of the deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19). In less than three months since the first cases were reported, the World Health Organization declared it a pandemic disease. Although several treatment and prevention strategies are currently under investigation, a continuous effort to investigate and develop effective cures is urgently needed. Thus, we performed molecular docking and structure-based virtual screening of libraries of approved drugs, antivirals, inhibitors of protein-protein interactions, and one million other small molecules to identify strong binders of the SARS-CoV-2 receptor-binding domain (RBD) that might interfere with the receptor recognition process, so as to inhibit the viral cellular entry. According to our screening and selection criteria, three approved antivirals (elbasvir, grazoprevir, and sovaprevir) and 4 other drugs (hesperidin, pamaqueside, diosmin, and sitogluside) were identified as potent binders of the RBD. The binding of these molecules involved several RBD residues required for the interaction of the virus with its cellular receptor. Furthermore, this study also discussed the pharmacological action of the 4 non-antiviral drugs on hematological and neurological disorders that, in addition to inhibiting the viral entry, could be beneficial against the neurological disorders identified in COVID-19 patients. Besides, six other small-molecules were identified, with no pharmacological description so far, exhibiting strong binding affinities to the RBD that we believe worth being investigated as inhibitors of the SARS-CoV-2-receptor interaction.

Hidden in Plain Sight: Natural Products of Commensal Microbiota as an Environmental Selection Pressure for the Rise of New Variants of SARS‐CoV‐2

“…These functional groups are present in other ligands like terpenes and drugs, which are predicted to bind to the same binding pocket in the RBD. [ 31 , 32 ] Additionally, these functional groups are present in other bile acids [33] and the drug Corilagin, [34] which are shown to interfere with the RBD binding to the ACE2 receptor in biochemical assays. The predicted binding pocket for NPs like bile acids and NRPs includes Asn501 (N501) (Figures 3 a‐b and Supporting Figures S1–S4).…”

Free Energy Landscapes and Residue Network Analysis for Six SARS-CoV-2 Targets in Complex with Plausible Phytochemical Inhibitors from Withania Somnifera: 1 µS Molecular Dynamics Simulations

“…The high recurrence value obtained for the phytochemical implies that phytochemical binding can affect the interactions required in the RBD region, to bind to human ACE2 receptor. It can be said here that Phe486, Tyr505, Asn501, Tyr489, Gln493, Leu455 were reported to form strong interactions with the ACE2 receptor (Behloul et al, 2021). Therefore, disruption of allosteric interactions of these residues upon phytochemical binding can result in its inhibition to bind to ACE2 receptor.…”

Reappraisal of Dietary Phytochemicals for Coronavirus Infection: Focus on Hesperidin and Quercetin

“…Various authors have confirmed the affinity of hesperidin for the RBD fragment of the spike protein and its ability to hinder the binding with ACE2 or to make the interaction unstable (Figure 3) [52,53]. The anchoring of hesperidin is stabilised by two hydrogen bonds (shown with green lines in Figure 3) with the amino acids Phe457 and Glu455 on the spike protein.…”