Structure-activity relationships of GPR120 agonists based on a docking simulation.

Area of Science:

• Pharmacology
• Molecular Biology
• Computational Chemistry

Background:

• G protein-coupled receptor 120 (GPR120) is expressed in the gut and adipose tissue, playing a role in free fatty acid-stimulated glucagon-like peptide-1 (GLP-1) secretion.
• Developing specific GPR120 agonists is crucial for therapeutic applications, particularly in metabolic and endocrine disorders.

Purpose of the Study:

• To synthesize and explore structure-activity relationships of novel GPR120 agonists.
• To evaluate the utility of computational docking simulations in predicting GPR120 agonistic activity.

Main Methods:

• Synthesis of NCG compounds derived from a peroxisome proliferator-activated receptor γ agonist.
• Development of a GPR120 homology model based on rhodopsin crystal structure for docking simulations.
• Calculation of hydrogen bonding energies between compounds and the GPR120 model.
• In vitro assays measuring extracellular signal-regulated kinase (ERK) activation, intracellular calcium responses, and GLP-1 secretion.
• In vivo administration of NCG21 in mice to assess plasma GLP-1 levels.

Main Results:

• Hydrogen bonding energies from docking simulations correlated well with GPR120 agonistic activity (R² = 0.73).
• NCG21 exhibited the lowest calculated hydrogen bonding energy and demonstrated potent ERK activation in a cloned GPR120 system.
• NCG21 effectively activated ERK, calcium signaling, and GLP-1 secretion in STC-1 cells and increased plasma GLP-1 levels upon colonic administration in mice.

Conclusions:

• The synthesized NCG compounds, particularly NCG21, show significant GPR120 agonistic activity.
• Docking simulations using a GPR120 homology model are a valuable tool for predicting the agonistic potential of novel compounds.
• NCG21 represents a promising GPR120 agonist with potential for modulating GLP-1 secretion.