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

Abstract

ABSTRACT-Recent progress in analyzing the structures and functions of G-protein coupled receptors (GPCRs) including > -adrenoceptors (>-ARs) has been made by pharmacological, physiological and molecular biological techniques. The three-dimensional (3D) structures, interaction sites with ligands and conformational changes of these receptor subtypes due to ligand binding are now better understood by the simulation of these receptors using computer-aided molecular modeling. Based on these techniques, numbers and conformations of amino acid sequences of each subtype (> 1-, >2-and >3-ARs) were defined and also interaction sites or modes of interaction between ligands and >-ARs could be analyzed three-dimensionally. In addition, simulation of 3D structures of > -ARs by molecular modeling could clearly determine the limited size, space or pocket for fitting with ligands. These studies will give some clues for the clarification of other GPCRs. Thus, this review summarizes current findings on chemical structures of ligands, amino acid sequences, 3D structures and important amino acids of >-AR subtypes for interacting with ligands obtained from mutagenesis, chimeric studies and molecular modeling techniques.

Molecular Dynamics Simulations Reveal Fundamental Role of Water As Factor Determining Affinity of Binding of β-Blocker Nebivolol to β2-Adrenergic Receptor

“…The previously derived RESP charges for the ligand (nebivolol) were imported into the AutoGrid module, and the receptor molecule (β 2 AR) was embedded into the docking-box. The position of the grid-box, located in the binding pocket of the βAR, corresponded to experimental data. , The Lamarckian Genetic Algorithm (LGA) was used for docking. The population size was set to 300 individuals, and the number of energy evaluations was set to 50 000 000.…”

“…The essential features of the binding site of the βAR have been characterized in several experimental studies. , These show that two amino acids, ASP113 and ASN312, are the key residues for binding. When analyzing the complexes, we focused on obtaining the experimentally observed hydrogen-bonding (H-bonding) patterns between these two essential amino acids and the H-bonding groups of nebivolol (Figure ).…”

Respiratory Effects of β-Adrenergic Receptor Blockers

“…Most phenylethanolamine exhibit agonistic properties, with the noticeable exception of sotalol, which possesses the ethanolamine side chain but shows antagonistic activity towards β1 and β2-ARs. The phenoxypropanolamine are mostly β1/ β2-AR antagonists and β3-AR agonists, but some drugs in this class, such as ICI 118551, CGP 20712A, and bupranolol, are β1/ β2/ β3-AR antagonists [13]. bioavailability, volume of distribution, lipid solubility, metabolism, route of excretion, etc.…”

Structure of the 2-isopropylaminoethanol isolated molecule: Conformational analysis and intramolecular interactions

“…For this reason, the knowledge of the structure of this compound is important as it provides a valuable contribution to the interpretation of the drug structure and, therefore, a tool to better understand its biological activity. Indeed, the behavior of a drug as agonist or antagonist depends on the fitting of its structure to that of the receptors [3]. The distance between the polar groups, which are the preferential sites for the interaction with the receptor, are markedly dependent on the conformation adopted by the drug molecule.…”