Development of original ligands for SUCNR1

G protein coupled receptors (GPCR) are the largest family of membrane receptors and currently the most successfully targeted protein for therapeutic purposes. However, many remain uncharacterized. For example, the succinate receptor 1 (SUCNR1, previously termed GPR91) and its endogenous ligand have been described as "metabolism sensor" because succinate (SA) is a citric acid cycle intermediate that is released outside the cell in case of oxygen deprivation. A lot of studies have addressed the roles of SUCNR1 and demonstrated its implication in the enhancement of immunity, retinal angiogenesis, hypertension. Collectively, these data suggest that SUCNR1 could be an attractive drug target in several pathologies. However, no synthetic agonists and very few ligands have been described. Therefore, there is a crucial need for small molecule tools in order to study its function and validate this receptor as a drug target
The objective of our project is to design, synthesize and characterize synthetic ligands for this receptor. Several diversified strategies have been envisaged accordingly. These include exploration of structure-activity relationships by means of organic synthesis or screening of virtual and chemical libraries. First, we have established an original screening methodology for Gi coupled receptors such as SUCNR1. Following the screening of a home-made library of succinic acid related molecules, we have established a pharmacophore that led to the identification of first original and synthetic SUCNR1 agonists. In addition, we constructed a model for the SUCNR1 binding site by homology modeling. This model will subsequently serve for a virtual screen of the ZINC database by docking. We plan to screen our collection of 50.000 molecules from a Diversity Oriented Strategy (DOS) library. This exploratory step will diversify the active chemical scaffolds and their pharmacological profiles.