Screening of repurposable natural products database to identify potent small-molecule inhibitors of SARS-CoV-2 spike glycoprotein

Abstract

Interaction between the RNA binding domain (RBD) of the SARS-CoV-2 spike glycoprotein (S-protein) and human angiotensin-converting enzyme 2 (ACE2) has been implicated in the viral entry into host cells. S-protein has become an essential constituent of the currently approved vaccines. S-protein may be inhibited by antibodies and peptides, but the inhibitions are usually characterised by instability and membrane impermeability. Hence, it is imperative to search for stable inhibitors. In this study, 2826 FDA-approved natural small-molecule drugs were screened against the pre-fusion SARS-CoV-2 S-protein (PDB 6VSB) using molecular docking and molecular dynamics simulations. Notably, lonafarnib, (-)-epicatechin gallate, melibiose, lactitol monohydrate and maltitol, showed strong binding interactions with the RBD of S-protein, with extra precision (XP) docking scores of -12.17, -11.67, -11.66, -11.30 and -10.74 kcal/mol respectively. It was referenced against remdesivir and ribavirin with XP docking scores of -9.10 and -6.05 kcal/mol respectively. Consistently, their respective molecular mechanics generalized Born surface area continuum solvation MMGB(SA) binding free energies, -18.48, -48.13, -30.01, -37.27 and -15.31 kcal/mol support their higher inhibitory potentials compared to the two references. They interacted with active site residues that are pharmacologically essential for blocking the S-protein-ACE2 that is responsible for SARS-CoV-2 infectivity, and displayed thermodynamic stability. The drugs showed promising potential as repurposable anti-SARS-CoV-2 candidates and therefore recommended for clinical studies