Design, synthesis and identification of ligands for SUCNR1 and GPR22

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) and its ligand succinic acid have been implicated in many pathophysiological conditions such as hypertension, ischemia reperfusion injuries (IRI) or retinal angiogenesis... Yet, no synthetic agonists and very few ligands have been described thus precluding its validation as a drug target. Another example of promising GPCR is GPR22 that has been highlighted as a potential drug target in heart failure and cardioprotection. However, this receptor is still orphan, with no known ligand.
The objective for this project is to design, synthesize and characterize synthetic ligands for these receptors. 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. In order to define comprehensive structure-activity relationships, we will synthesize several SUCNR1 agonists based on a general pharmacophore that we have already established. In addition, we constructed a model for the SUCNR1 binding site by homology modeling. Targeted mutagenesis and cell-based functional assays with diverse active compounds will be performed to validate it experimentally. This model will subsequently serve for a virtual screen of the ZINC database by docking in order to identify potential ligands. For the identification of additional active compounds, we have established an original screening methodology for Gi coupled receptors such as SUCNR1 and GPR22. We plan to screen our small molecule collections on these two receptors during the project. This exploratory step will diversify the active chemical scaffolds and their pharmacological profiles. Confirmed hits we be thoroughly characterized in our pharmacological assays.