Computational studies of the binding site of α 1A -adrenoceptor antagonists

Aimed at achieving a good understanding of the 3-dimensional structures of human α1A-adrenoceptor (α1A-AR), we have successfully developed its homology model based on the crystal structure of β2-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 α1A-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 α1A-AR antagonists and for guiding further mutagenesis studies.