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

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.

β -Adrenoceptors: Three-Dimensional Structures and Binding Sites for Ligands

“…These authors also indicated that derivatization of TM6 and TM7 by these photolabelled compounds suggests the folded conformation of these compounds in the ligand binding pocket. On the other hand, our laboratory deduced 3D structures of human >-ARs and profiles of >-AR antagonists binding by computer simulation based on the electron density map of rhodopsin (34,35). This modeling analysis supported the results of molecular biological-/pharmacological-experiments and further gave us some novel interesting suggestions.…”

“…This modeling analysis supported the results of molecular biological-/pharmacological-experiments and further gave us some novel interesting suggestions. We assumed that the amine, benzoic acid, indole methyl, (TM5) and Pro 236 (TM5) of >1-AR, respectively, by either hydrogen bonding or hydrophobic interactions (35). Thus, the analysis of interaction between ligands and receptors by this computer simulation will give us newer information of highly and more precise 3D structures of >-AR subtypes and/or different interactions in these subtypes.…”

Assessment of Affinities of Propranolol and Bopindolol to Membranes from COS-7 Cell Transiently Transfected with Beta-1- and Beta-2-Adrenoceptors Using a Radioligand-Binding Assay Method

“…The functional groups of propranolol and bopindolol involved in interactions with ß-ARs were amino, benzoic, indole methyl, naphthyl, isopropyl, t-butyl alcohol and indole ring groups, and these Nakamura/Suzuki/Ohnuki/Hattori/ Watanabe/Kurose/Nagao/Nagatomo functional groups may interact with several amino acid residues in helices 3, 4, 5 and 6 of ß 1 -and ß 2 -ARs. Our previous studies [1,2] using molecular modeling also suggested that these functional groups of propranolol possibly interact with Try134, Ala343, Phe340, Pro339, Val137, Cys336, Asp138, Leu237 and Ser190 in transmembrane helices 3, 4, 5 and 6 of ß 1 -ARs. These studies suggested that these amino acid residues in each helix of ß 1 -ARs may be important for binding with ligands and for manifestation of ß-blocking actions.…”

“…Previously [1,2] we hypothesized that some functional groups of ß-blockers, the basic chemical structure of which is that of aryloxypropanolamine, are very important for interactions with amino acids in the seven transmembrane helices of ß-ARs. The functional groups of propranolol and bopindolol involved in interactions with ß-ARs were amino, benzoic, indole methyl, naphthyl, isopropyl, t-butyl alcohol and indole ring groups, and these Nakamura/Suzuki/Ohnuki/Hattori/ Watanabe/Kurose/Nagao/Nagatomo functional groups may interact with several amino acid residues in helices 3, 4, 5 and 6 of ß 1 -and ß 2 -ARs.…”

“…In our previous studies [1,2], molecular modeling suggested three-dimensional interactions and binding models (hydrogen or hydrophobic bonds) between ß-blockers and G-protein-coupled ß 1 -or ß 2 -adrenoceptors (ß-ARs) with seven transmembrane domains. These results of mo- lecular modeling identified possible important functional groups in chemical structures of ß-blockers and amino acid residues in G-protein-coupled and seven-transmembrane helix of ß-ARs.…”