Computational studies of the binding site of alpha1A-adrenoceptor antagonists.
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.
Li
Minyong
M
Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30302, USA. mli@gsu.edu
Fang
Hao
H
Du
Lupei
L
Xia
Lin
L
Wang
Binghe
B
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
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