Identification of Binding Sites of Bopindolol and Its Two Metabolites with β1-Adrenoceptors by Molecular Modeling: Comparison with β2 Adrenoceptors

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Abstract
This study was designed to examine the importance of interaction in the bindings of nonselective β-blockers to β1-adrenoceptors (β1-ARs) as compared with β2-ARs, using molecular modeling. The β-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 β1-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 β1-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 β2-ARs. Thus, the results of the present study suggested that although Ala343 and Val137 of β1-AR among these amino acids were different from those of β2-AR, the interactions at the same sites between ligands and amino acids of β1-AR as those of β2-ARs may occur because these drugs are nonselective.