title: Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies.
abstract: TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists.
authors.affiliation: Institut de Genetique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/INSERM/ULP, Illkirch, France.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.forename: Mizuho
authors.initials: M
authors.lastname: Une
authors.forename: Alan F
authors.initials: AF
authors.lastname: Hofmann
authors.forename: Régis
authors.initials: R
authors.lastname: Saladin
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006728:Hormones / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001647:Bile Acids and Salts; C473772:GPBAR1 protein, human; D006728:Hormones; D008024:Ligands; D043562:Receptors, G-Protein-Coupled