title: Molecular field analysis and 3D-quantitative structure-activity relationship study (MFA 3D-QSAR) unveil novel features of bile acid recognition at TGR5.
abstract: Bile acids regulate nongenomic actions through the activation of TGR5, a membrane receptor that is G protein-coupled to the induction of adenylate cyclase. In this work, a training set of 43 bile acid derivatives is used to develop a molecular interaction field analysis (MFA) and a 3D-quantitative structure-activity relationship study (3D-QSAR) of TGR5 agonists. The predictive ability of the resulting model is evaluated using an external set of compounds with known TGR5 activity, and six bile acid derivatives whose unknown TGR5 activity is herein assessed with in vitro luciferase assay of cAMP formation. The results show a good predictive model and indicate a statistically relevant degree of correlation between the TGR5 activity and the molecular interaction fields produced by discrete positions of the bile acid scaffold. This information is instrumental to extend on a quantitative basis the current structure-activity relationships of bile acids as TGR5 modulators and will be fruitful to design new potent and selective agonists of the receptor.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.forename: Alberto
authors.initials: A
authors.lastname: Massarotti
authors.forename: Roberto
authors.initials: R
authors.lastname: Nuti
authors.forename: Emiliano
authors.initials: E
authors.lastname: Rosatelli
authors.forename: Paola
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D021621:Imaging, Three-Dimensional; D008956:Models, Chemical; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled