Molecular understanding of GPR120 agonist binding using homology modeling and molecular dynamics

The toll of type-2 diabetes and associated complications are continues, efforts to identify possible targets are ongoing. Free fatty acid receptor 4 (FFAR4/GPR120) has been recently identified to be a promising therapeutic target for a group of metabolic associated disorders. For the prevention of type 2 diabetes, significant scientific and commercial interest has been developed around GPR120 and its role. Due to the unavailability of a crystal structure, the interaction dynamics of GPR120 agonists were not yet determined to date. In the present study, we constructed the homology model for GPR120 and validated using available mutational data and molecular dynamics simulation, and explored its binding modes with known small molecule agonists. So, sixteen propionic acid derivatives as GPR120 agonists were collected to elucidate their binding modes. Experiential and theoretical studies suggested that the carboxylic group of ligands interact with Arg99, which is an important interaction for GPR120 activation. However, earlier reports also suggest that this interaction is not stable during the molecular dynamics simulation, which contradicts the experimental observations. Evidently, to refute this, we got a stable interaction of Arg99 with TUG891 and other recently reported 15 GPR120 agonists. In addition, we have also observed that in 1 µs molecular dynamics simulation Arg183 present in ECL2 tends to come inside and interact with ligand. Molecular dynamics simulation study provides a list of key hotspot residues which play an important role in ligand binding. The homology model and results provides could be further utilized as a powerful template to accelerate the research in this field.