Discovering small compound modulators for Secretin receptor

Abstract

G protein-coupled receptors (GPCRs) are pharmacologically vital due to their role in several diseased conditions like osteoporosis, obesity, cancer, neurodegeneration, diabetes, cardiovascular disease and even psychiatric disorders. Class B GPCRs are also known as Secretin like receptors and are composed of 15 highly attractive therapeutic targets. These receptors are known to be activated by the secretin peptide, which has a short plasma half-life and therefore, there is a need to develop a non-peptide agonist and/or antagonist. The secretin receptor (SCTR) is involved in many physiological functions such as HCO3- release from the pancreas, fatty acid absorption, and water homeostasis. Other studies also suggest that secretin may improve the cardiac profile and it can also mediate insulin secretion upon its action on pancreatic beta cells. We have developed a 3D model of SCTR [1] and have successfully expressed and purified the N terminal extracellular domain of SCTR. In this study, we aim to develop a small compound modulator for SCTR to be utilized as a possible therapeutic molecule. We recently reported that both the N and C terminal regions of the peptide ligand are essential for its binding to the receptor [1]. Furthermore, it is well acknowledged that the peptide ligand binds to the N terminal domain. Aided by the recent finding of the endogenous agonistic mechanism of activation [2], we aim to use the information in developing a direct agonistic molecule for the receptor and also to study the mechanism of receptor activation. We have found four SCTR small compound modulators by using the SCTR 3D model. The model was used to map the active site and develop a pharmacophore model to screen a library of 1.5 billion compounds which yielded 810 compounds, further screened via virtual docking. Further, about 30 compounds were tested In-vitro for their capability to modulate SCTR. Lastly, we now found four small compound modulators of SCTR.