Cross evaluation of different classes of alpha-adrenergic receptor antagonists to identify overlapping pharmacophoric requirements

Structurally dispersive classes of drugs targeting identical receptor binding site can serve as a source of information in the design of novel drug candidates. Their comparative cross structural features can be utilized toward optimization of receptor-ligand interactions. Five established alpha-adrenergic receptors antagonists were selected as representative compounds of their respective classes. The selected antagonists are Phenoxybenzamine, Phentolamine, Prazosin, Ergoloid Mesylate and Labetalol. A small library of 1000 molecules, 200 from each class, were submitted to molecular docking in the antagonist binding site of alpha-adrenergic receptor. The present work includes homology modeling of alpha-adrenergic receptor using SPDBV and its structure validation from Procheck. The molecule library was developed using drug likeness filters (Lipinski's rules). Flexible molecular docking was performed using MVD (Molegro Virtual Docker) after receptor and ligand preparation. The conclusive outcome of the present work is identification of antagonist binding sites of the alpha-1 (α1)-adrenergic receptor exclusively as hydrophobic due to presence of the amino acids Val 107, Val 157, Asp 106, Ile 157, Ser 158, Ser 192, Ala 189, Phe 288 and Phe 289.The amino acids identified were found crucial to identify pharmacophoric features for alpha-1 (α1)-adrenergic receptor and antagonists. Results also include identification of new molecule (PubChem ID 10289950) similar to Ergoloid Mesylate with re-rank score −113.571. The present work explains successive workflow of homology modeling, flexible molecular docking, and pharmacophoric features identification.