title: Structure-activity relationships of GPR120 agonists based on a docking simulation.
abstract: GPR120 is a G protein-coupled receptor expressed preferentially in the intestinal tract and adipose tissue, that has been implicated in mediating free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion. To develop GPR120-specific agonists, a series of compounds (denoted as NCG compounds) derived from a peroxisome proliferator-activated receptor γ agonist were synthesized, and their structure-activity relationships as GPR120 agonists were explored. To examine the agonistic activities of these newly synthesized NCG compounds, and of compounds already shown to have GPR120 agonistic activity (grifolic acid and MEDICA16), we conducted docking simulation in a GPR120 homology model that was developed on the basis of a photoactivated model derived from the crystal structure of bovine rhodopsin. We calculated the hydrogen bonding energies between the compounds and the GPR120 model. These energies correlated well with the GPR120 agonistic activity of the compounds (R(2) = 0.73). NCG21, the NCG compound with the lowest calculated hydrogen bonding energy, showed the most potent extracellular signal-regulated kinase (ERK) activation in a cloned GPR120 system. Furthermore, NCG21 potently activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express GPR120 endogenously. Moreover, administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Taken together, our present study showed that a docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds.
authors.affiliation: Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hara
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kimura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Adachi
authors.forename: Takeo
authors.initials: T
authors.lastname: Awaji
authors.forename: Masaji
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
mesh_terms: D000595:Amino Acid Sequence; D000631:Aminopyridines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010654:Phenylbutyrates / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: C553920:4-(4-(2-(phenyl-2-pyridinylamino)ethoxy)phenyl)butyric acid; D000631:Aminopyridines; C498007:FFAR4 protein, mouse; D008024:Ligands; D010654:Phenylbutyrates; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium