title: Modeling and simulation studies of human β3 adrenergic receptor and its interactions with agonists.
abstract: β3 adrenergic receptor (β3AR) is known to mediate various pharmacological and physiological effects such as thermogenesis in brown adipocytes, lipolysis in white adipocytes, glucose homeostasis and intestinal smooth muscle relaxation. Several efforts have been made in this field to understand their function and regulation in different human tissues and they have emerged as potential attractive targets in drug discovery for the treatment of diabetes, depression, obesity etc. Although the crystal structures of Bovine Rhodopsin and β2 adrenergic receptor have been resolved, to date there is no three dimensional structural information on β3AR. Our aim in this study was to model 3D structure of β3AR by various molecular modeling and simulation techniques. In this paper, we describe a refined predicted model of β3AR using different algorithms for structure prediction. The structural refinement and minimization of the generated 3D model of β3AR were done by Schrodinger suite 9.1. Docking studies of β3AR model with the known agonists enabled us to identify specific residues, viz, Asp 117, Ser 208, Ser 209, Ser 212, Arg 315, Asn 332, within the β3AR binding pocket, which might play an important role in ligand binding. Receptor ligand interaction studies clearly indicated that these five residues showed strong hydrogen bonding interactions with the ligands. The results have been correlated with the experimental data available. The predicted ligand binding interactions and the simulation studies validate the methods used to predict the 3D-structure.
authors.affiliation: School of Biotechnology, Gautam Buddha University, Greater Noida, India. shaktis@gbu.ac.in
authors.forename: Shakti
authors.initials: S
authors.lastname: Sahi
authors.forename: Parul
authors.initials: P
authors.lastname: Tewatia
authors.forename: Balwant K
authors.initials: BK
authors.lastname: Malik
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000814:Aniline Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000928:Antidepressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D021621:Imaging, Three-Dimensional; D007700:Kinetics; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010940:Plant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D022702:Receptors, Adrenergic, beta-3 / Q000737:chemistry* / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C581202:2-(cyclohexyloxy)-4-(4-(2-((2-hydroxy-2-(4-methoxyphenyl)ethyl)amino)ethyl)phenyl)-N-methanesulfonybenzamide; C568534:ADRB3 protein, human; D058667:Adrenergic beta-3 Receptor Agonists; D000814:Aniline Compounds; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001565:Benzoates; D001713:Biphenyl Compounds; D006023:Glycoproteins; D050505:Mutant Proteins; D010940:Plant Proteins; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; C523977:solabegron; C076252:amibegron