title: Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism.
abstract: Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Festa
authors.affiliation: Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.|Università della Svizzera Italiana (USI), Faculty of Informatics, Institute of Computational Science, via G. Buffi 13, CH-6900 Lugano, Switzerland.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
mesh_terms: D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015870:Gene Expression; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D008095:Lithocholic Acid