Study of the orphan GPR21 towards therapeutics for metabolic disorders

Abstract

Since G-Protein Coupled Receptors (GPCRs) are engaged in a variety of signal transduction pathways in many pathophysiological situations, they are important targets for the development of novel drugs. GPR21 is a constitutively active orphan GPCR, which means that it remains in an active state even in the absence of an intrinsic ligand. GPR21 is involved in insulin sensitivity regulation. This suggests that it has potential as a therapeutic target for metabolic diseases, including type 2 diabetes. The small molecules GRA2 and UCSF924 have been found to interact with GPR21, however their binding mechanisms still remain unclear. Here we propose interaction scenarios between these ligands and GPR21, using homology modelling and molecular docking methods. Our results show that models with refined extracellular loop 2 (ECL2) regions, especially the ones where the whole loop or immersed region (residues 169- 178) is refined, display enhanced druggability and better docking outcomes with GRA2 and UCSF924. In the immersed region and whole loop refined models we observed that the residue H174ECL2, which is important for the receptor activation, is displaced from the orthosteric pocket. Additionally, AlphaFold predictions suggest a side pocket between TM1, TM2, and TM7, similar to that of GPR52, where both ligands could form stable hydrophobic interactions. These findings indicate that GRA2 and UCSF924 are likely to bind either within the orthosteric pocket or the side pocket, reducing GPR21’s constitutive activity and therefore act as GPR21 inhibitors. Our models provide a basis for further molecular dynamics simulations and in vitro studies to confirm these interactions and explore the therapeutic potential of targeting GPR21.