Identification of binding sites of bopindolol and its two metabolites with β1-adrenoceptors by molecular modeling:: Comparison with β2 adrenoceptors

This study was designed to examine the importance of interaction in the bindings of nonselective beta-blockers to beta(1)-adrenoceptors (beta(1)-ARs) as compared with beta(2)-ARs, using molecular modeling. The beta-blockers used in this study were bopindolol [4-(benzoyloxy-3-t-butylaminopropyl)-2-methylindol hydrogen malomate], its two metabolites [18-502 - hydrolyzed bopindolol or 4-(3-t-butylamino-2-hydroxypropoxy)-2-methyl indole - and 20-785 - 4-(3-t-butylaminopropoxy)-2-carboxyl indole], and propranolol. Molecular modeling was performed on an Indigo2 workstation (Silicon Graphic) using Discover/insight II (Molecular Simulations) software. Through molecular modeling, possible binding sites for these drugs were suggested to lie between helices 3, 4, 5, and 6 of the beta(1)-AR. The amine, benzoic acid, indole methyl, t-butyl, phenyl, and indole functional groups of bopindolol possibly interact with Asp138 (transmembrane - TM - 3), Ser190 (TM 4), Ala343 (TM 6), Val137 (TM 3), Pro339 (TM6), Cys336 (TM 4), Leu237 (TM 5), and Pro236 (TM 5) of beta(1)-AR, respectively, by either hydrogen bonding or hydrophobic interactions. in addition, 18-502, 20-785, and propranolol also interacted with sites at the same positions as those of beta(2)-ARs. Thus, the results of the present study suggested that although Ala343 and Val137 of beta(1)-AR among these amino acids were different from those of beta(2)-AR, the interactions at the same sites between ligands and amino acids of beta(1)-AR as those of beta(2)-ARs may occur because these drugs are nonselective.