Study of the selectivity of alpha(1)-adrenergic antagonists by molecular modeling of alpha(1a)-, alpha(1b)-, and alpha(1d)-adrenergic receptor subtypes and docking simulations

Abstract

Modeling of alpha(1a), alpha(1b), and alpha(1d) 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. alpha(1)-Adrenergic antagonists with the highest order of selectivity 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 subtype complexes were then used for correlation with selectivity on different alpha(1)-adrenergic subtypes. Good correlations were obtained for most receptor subtype-selectivity pairs: (1) using PMF scores calculated for ligands in complex with alpha(1a)-receptor subtype, r = 0.7503 for alpha(1a/1b) and r = 0.6336 for alpha(1a/1d) selectivity; (2) using PMF scores calculated for ligands in complex with alpha(1b) receptor subtype, r = 0.7632 for alpha(1a/1b) and r = 0.7061 for alpha(1b/1d) selectivity; (3) using PMF scores for ligands in complex with alpha(1d) receptor subtype, r = 0.7377 for alpha(1a/1d) and r = 0.9913 for alpha(1b/1d) selectivity.