Molecular Modelling Reveals Eight Novel Druggable Binding Sites in SARS-CoV-2’s Spike Protein

Abstract

<p>Spike glycoprotein (S), one of the signature proteins of the SARS-CoV-2, initiates the membrane fusion and virus entry to the host cell. The S protein’s key role in virus viability makes it an attractive candidate for drug design studies. Besides the recent structural characterization of the S protein, information fundamental to drug design such as possible binding sites or molecular fragments with high affinity towards the protein is unknown. We explored the druggability of this protein, focusing on its S1 and S2 domains. We performed virtual screening studies on both closed and open forms of the protein, using both cryo-EM structures and geometries obtained from molecular dynamic simulations. We targeted 20 distinct ligand binding centres with a set of about 9,000 molecules. Our docking calculations followed by molecular mechanics-based refinement of ligand/protein complexes led us to detect eight binding sites that were so far undocumented. By further focusing on a subset of approximately 1,000 approved and marketed drugs, we aimed at suggesting a new direction for drug repurposing strategies that were not considered so far. Within this approved set, our best hits include a number of antibacterial and antiviral drugs (e.g., Streptomycin, Nelfinavir), which were not yet investigated clinically in treating COVID-19. We also identified some molecules (e.g., folic acid, Famotidine) that were already suggested to be effective towards SARS-CoV-2, yet without molecular explanation. Our results also indicate a great affinity of SARS-CoV-2’s S protein towards nucleoside analogues, either approved or experimental.</p>