title: Computational study of antagonist/alpha1A adrenoceptor complexes--observations of conformational variations on the formation of ligand/receptor complexes.
abstract: As selective antagonist inhibition may relieve the symptoms of benign prostatic hyperplasia, we have examined the interactions of antagonists including quinazoline and imidazolidinium/guanidinium compounds complexed with a homology model of the alpha(1A) adrenoceptor. Our approach involves docking of ligands of various structural classes followed by molecular dynamics simulations of antagonist/receptor complexes, which demonstrates that different structural classes of antagonist induce different receptor conformations upon binding with particular variations noted in the conformation of TM-V. Subsequently, we examined the interactions and the conformational flexibility of alpha(1) and alpha(1A) adrenoceptor antagonists, with the ligand-induced receptor conformers. This study indicated that a receptor conformation induced by one structural class of antagonist is not suitable for direct screening of another class. Our analysis indicates that computational high-throughput screening is likely to give inaccurate data on binding and selectivity and such studies need to consider conformational changes in the receptor.
authors.affiliation: School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Kinsella
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
authors.forename: Graeme W
authors.initials: GW
authors.lastname: Watson
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry*; D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1