In silico investigation of β-lactams as inhibitors of the spike protein receptor binding domain (RBD) of SARS-CoV-2

Abstract Continuous efforts are underway to address COVID-19’s adverse impacts, complicated by the emergence of SARS-CoV-2 variants. The spike protein, essential for viral entry via hACE2 binding, remains a key target for drug development. This study investigates twelve β-lactam compounds as potential sRBD inhibitors through in-silico methods, including molecular docking, molecular dynamics simulations, MM/GBSA and ADME property analysis. Out of the twelve, nine compounds adhered to Lipinski’s rule, while the other three and the references, Cefsulodin and Ceftazidime, stood as exceptions. Molecular docking across Wuhan, Delta, and Omicron variants, followed by 100 ns Molecular Dynamic (MD) simulations, revealed three promising inhibitors: compounds 5 and 6 for Wuhan and Delta and compound 3 for Omicron. The complexes that demonstrated stability in MD simulations also showed favourable protein–ligand interaction energies and binding free energies in the MM/GBSA analysis. DFT calculations assessed the possible reactions between β-lactams and active-site amino acids. These findings support the potential of our designed β-lactam compounds against SARS-CoV-2 variants, meriting further experimental evaluation.