gw9508 and diphenyl

The free fatty acid receptor 1 (FFA1) enhances the glucose-stimulated insulin secretion without the risk of hypoglycemia. However, most of FFA1 agonists have a common biphenyl moiety, leading to a relative deprivation in structure types. Herein, we describe the exploration of non-biphenyl scaffold based on the co-crystal structure of FFA1 to increase additional interactions with the lateral residues, which led to the identification of lead compounds 3 and 9. In induced-fit docking study, compound 3 forms an edge-on interaction with Trp150 by slightly rotating the indole ring of Trp150, and compound 9 has additional hydrogen bond and δ-π interactions with Leu135, which demonstrated the feasibility of our design strategy. Moreover, lead compounds 3 and 9 revealed improved polar surface area compared to GW9508, and have considerable hypoglycemic effects in mice. This structure-based study might inspire us to design more promising FFA1 agonists by increasing additional interactions with the residues outside of binding pocket.

Topics: Animals; Binding Sites; Biphenyl Compounds; Diabetes Mellitus, Type 2; Drug Design; Glucose Tolerance Test; Humans; Hydrogen Bonding; Hypoglycemic Agents; Male; Methylamines; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Propionates; Protein Structure, Tertiary; Receptors, G-Protein-Coupled; Structure-Activity Relationship