Exploration of heterocyclic ligands binding to the RBD-angiotensin interface in the sars-cov-2 omicron variant: a computational study

The SARS-CoV-2 Omicron variant, characterized by a multitude of mutations within its receptor-binding domain (RBD), demonstrates an augmented affinity for the human ACE2 receptor, thereby enhancing its infectivity and capacity for immune evasion. This investigation explores the efficacy of heterocyclic compounds to impede the RBD-ACE2 interaction through a high-throughput blind docking methodology. Method. A comprehensive total of 63 heterocyclic ligands were subjected to docking against the Omicron RBD employing AutoDock, with 5,000 iterations conducted for each compound. Five pivotal binding regions—Mpocket, Apocket, and the accessory binding sites ABS-1, ABS-2, and ABS-3—were delineated and assessed in relation to binding free energy and docking frequency. Result. Mpocket exhibited the most advantageous binding profile, characterized by the lowest average binding energy (-4.00 kcal/mol) and a high docking frequency (27.85%). ABS-1 further demonstrated significant accessibility (33.78% of total runs). Compounds such as Phenoxazole (FEB = -6.41 kcal/mol), Acridine (FEB = -5.94 kcal/mol), and Phenazine (FEB = -5.67 kcal/mol) revealed pronounced binding affinities and consistent interactions, particularly with the residues SER 496 and ARG 403. Two-dimensional (2D) and three-dimensional (3D) interaction analyses supported the structural compatibility of these ligands with Mpocket, while ABS-2 surfaced as a promising secondary binding site due to its elevated ligand accessibility. Conclusion. These outcomes endorse the potential of heterocyclic scaffolds as inhibitors aimed at the RBD-ACE2 interface binding sites.