Computational Drug Repurposing Studies on the ACE2-Spike (RBD) Interface of SARS-CoV-2

The novel coronavirus is known to enter the cell by binding to the human transmembrane protein Angiotensin-Converting Enzyme 2 (ACE2). The S(Spike)-glycoprotein of the SARS-CoV-2 forms a complex with the ACE2. Thus, the S-glycoprotein is one of the hot targets, as it forms the first line of contact between the virus and the human cell. Drug repurposing would help in identifying drugs that are safe and have no or fewer side effects. Hence, in addition to the Food and Drug Administration (FDA) approved molecules the compounds from natural sources were also considered. The current study includes docking and simulations of the FDA approved molecules and phytochemicals from Indian medicinal plants, targeting the ACE2-Spike protein complex. Rutin DAB10 and swertiapuniside were obtained as the top-ranked drugs from these two databases, respectively. The molecular dynamics simulations of ligand-free, rutin DAB10-bound, and swertiapuniside-bound ACE2-Spike complex revealed crucial ACE2-Spike interface residues forming strong interactions with the two ligands molecules. This may infer, that they may affect the ACE2 and spike binding. The conformational flexibility in the drug-binding pocket was captured using the RMSD-based clustering of the ligand-free simulations. An ensemble docking was performed wherein the two databases were docked on each of the representatives of ACE2-Spike obtained through clustering. The potential phytochemicals identified belonged to Withania somnifera, Swertia chirayita, Tinospora cordifolia, Andrographis paniculata, Piper longum, and Azadirachta indica. The FDA molecules identified were rutin DAB10, fulvestrant, cefoperazone acid, escin, chlorhexidine diacetate, echinacoside, capreomycin sulfate, and elbasvir.