Design and assay of Regulator G-protein Signaling 2 inhibitors

Regulation of G Protein Signaling(RGS), regulates the G Protein-Coupled Receptor(GPCR) and helps control the functions of the receptors. RGS proteins are expressed in most tissues, divided into four subfamilies, and work by speeding up the hydrolysis of GTP--> GDP, effectively turning off the signal mediated by the GPCR. RGS2 is a member of the RGS family of proteins, involved in regulating blood pressure in humans. Its overexpression, however, is associated with some disease states including Bartter's/Gitelman's syndrome and can be linked to increased aggression in males. Most importantly, RGS2 is involved in cancer metastasis, especially in prostate and breast cancers. Inhibiting the function of the RGS2, there, is important to stop metastasis of those types of cancers. For this study, creating an RGS2 inhibitor was the focus. A pharmacophore was created by utilizing the unique "switch region" at the binding interface of RGS2 and the Gq subunit of the G protein. Visual Molecular Dynamics (VMD) was used to extract the pharmacophore model from structure 2V4Z and PHASE was used for virtual screening of chemical databases. Out of the thousands of hits retrieved, 10 were chosen for experimental testing where compound AJ-1 was shown to be the most potent with an IC5 1.45nM.