The COVID-19 pandemic has had deleterious effects on the world and demands urgent measures to find therapeutic agents to combat the current and related future outbreaks. The entry of SARS-CoV-2 into the host's cell is facilitated by the interaction between the viral spike receptor-binding domain (sRBD) and the human angiotensin-converting enzyme 2 (hACE2). Although the interface of sRBD involved in the sRBD-hACE2 interaction has been projected as a primary vaccine and drug target, currently no small-molecule drugs have been approved for covid-19 treatment targeting sRBD. Herein structure-based virtual screening and molecular dynamics (MD) simulation strategies were applied to identify novel potential small-molecule binders of the SARS-CoV-2 sRBD from an sRBD-targeted compound library as leads for the development of anti-COVID-19 drugs. The library was initially screened against sRBD by using the GOLD docking program whereby 19 compounds were shortlisted based on docking scores after using a control compound to set the selection cutoff. The stability of each compound in MD simulations was used as a further standard to select four hits namely T4S1820, T4589, E634-1449, and K784-7078. Analyses of simulations data showed that the four compounds remained stably bound to sRBD for ≥ 80 ns with reasonable affinities and interacted with pharmacologically important amino acid residues. The compounds exhibited fair solubility, lipophilicity, and toxicity-propensity characteristics that could be improved through lead optimization regimes. The overall results suggest that the scaffolds of T4S1820, E634-1449, and K784-7078 could serve as seeds for developing potent small-molecule inhibitors of SARS-CoV-2 receptor binding and cell entry.Communicated by Ramaswamy H. Sarma.
Keywords: COVID-19; SARS-CoV-2; molecular dynamics; spike receptor-binding domain; structure-based virtual screening.