title: Computational studies of the binding site of alpha1A-adrenoceptor antagonists.
abstract: Aimed at achieving a good understanding of the 3-dimensional structures of human alpha1A-adrenoceptor (alpha1A-AR), we have successfully developed its homology model based on the crystal structure of beta2-AR. Subsequent structural refinements were performed to mimic the receptor's natural membrane environment by using molecular mechanics (MM) and molecular dynamics (MD) simulations in the GBSW implicit membrane model. Through molecular docking and further simulations, possible binding modes of subtype-selective alpha1A-AR antagonists, Silodosin, RWJ-69736 and (+)SNAP-7915, were examined. Results of the modeling and docking studies are qualitatively consistent with available experimental data from mutagenesis studies. The homology model built should be very useful for designing more potent subtype-selective alpha1A-AR antagonists and for guiding further mutagenesis studies.
authors.affiliation: Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30302, USA. mli@gsu.edu
authors.forename: Minyong
authors.initials: M
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
authors.forename: Lupei
authors.initials: L
authors.lastname: Du
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry*; D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000737:chemistry; D011487:Protein Conformation; D011728:Pyridones / Q000737:chemistry; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D010879:Piperazines; D011728:Pyridones; C410962:RWJ 69736; D018340:Receptors, Adrenergic, alpha-1; D018343:Receptors, Adrenergic, beta-2; C095285:silodosin