Structure-based design of free fatty acid receptor 1 agonists bearing non-biphenyl scaffold

Add time:08/27/2019    Source:sciencedirect.com

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.

We also recommend Trading Suppliers and Manufacturers of 2-Ethyl-2,3-dihydrobenzofuran-2-carboxylic acid (cas 111080-50-3). Pls Click Website Link as below: cas 111080-50-3 suppliers

Prev:Enantioselective synthesis of 2-ethyl-2,3-dihydrobenzofuran carboxylic acid, direct precursor of (+)-efaroxan, from a Baylis–Hillman adduct
Next:ReviewRelevance, structure and analysis of ferulic acid in maize cell walls)