Computationally identified novel agonists for GPRC6A.

• Main Authors: Min Pi, Karan Kapoor, Ruisong Ye, Dong-Jin Hwang, Duane D Miller, Jeremy C Smith, Jerome Baudry, L Darryl Quarles
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2018-01-01
• Series: PLoS ONE
• Online Access: http://europepmc.org/articles/PMC5912754?pdf=render

New insights into G protein coupled receptor regulation of glucose metabolism by β-cells, skeletal muscle and liver hepatocytes identify GPRC6A as a potential therapeutic target for treating type 2 diabetes mellitus (T2D). Activating GPRC6A with a small molecule drug represents a potential paradigm-shifting opportunity to make significant strides in regulating glucose homeostasis by simultaneously correcting multiple metabolic derangements that underlie T2D, including abnormalities in β-cell proliferation and insulin secretion and peripheral insulin resistance. Using a computational, structure-based high-throughput screening approach, we identified novel tri-phenyl compounds predicted to bind to the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A. Experimental testing found that these compounds dose-dependently stimulated GPRC6A signaling in a heterologous cell expression system. Additional chemical modifications and functional analysis identified one tri-phenyl lead compound, DJ-V-159 that demonstrated the greatest potency in stimulating insulin secretion in β-cells and lowering serum glucose in wild-type mice. Collectively, these studies show that GPRC6A is a "druggable" target for developing chemical probes to treat T2DM.