Study of the selectivity of α1-adrenergic antagonists by molecular modeling of α1a-, α1b-, and α1d-adrenergic receptor subtypes and docking simulations

Abstract

Modeling of a1a, a1b, and a1d adrenergic receptor subtypes has been performed using InsightII software and bovine rhodopsin as a template. Adrenaline and noradrenaline, as endogenous agonists, were docked to validate the developed models, explore the putative binding sites, and calculate relative docking scores. a1-Adrenergic antagonists with the highest order of selec- tivity and activity at specific receptor subtypes were then chosen for docking into the corresponding receptor models. Docking simulations were performed using the FlexX module implemented in the Sybil program. PMF scoring functions of the obtained complexes calculated as relative to PMF scoring functions for noradrenaline-receptor sub- type complexes were then used for correlation with selectivity on different a1-adrenergic subtypes. Good cor- relations were obtained for most receptor subtype- selectivity pairs: (1) using PMF scores calculated for ligands in complex with a1a-receptor subtype, r = 0.7503 for a1a/1b and r = 0.6336 for a1a/1d selectivity; (2) using PMF scores calculated for ligands in complex with a1b receptor subtype, r = 0.7632 for a1a/1b and r = 0.7061 for a1b/1d selectivity; (3) using PMF scores for ligands in complex with a1d receptor subtype, r = 0.7377 for a1a/1d and r = 0.9913 for a1b/1d selectivity.