Computationally identified novel agonists for GPRC6A

Min Pi, Karan Kapoor, Ruisong Ye, Dong Jin Hwang, Duane Miller, Jeremy C. Smith, Jerome Baudry, Leigh Quarles

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere0195980
JournalPloS one
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2018

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agonists
insulin secretion
Insulin
Medical problems
noninsulin-dependent diabetes mellitus
Glucose
Type 2 Diabetes Mellitus
glucose
Dionaea muscipula
Venus
Lead compounds
Functional analysis
Chemical modification
Cell proliferation
cells
G-Protein-Coupled Receptors
Metabolism
insulin resistance
Diptera
Vascular Resistance

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Computationally identified novel agonists for GPRC6A. / Pi, Min; Kapoor, Karan; Ye, Ruisong; Hwang, Dong Jin; Miller, Duane; Smith, Jeremy C.; Baudry, Jerome; Quarles, Leigh.

In: PloS one, Vol. 13, No. 4, e0195980, 01.04.2018.

Research output: Contribution to journalArticle

Pi, M, Kapoor, K, Ye, R, Hwang, DJ, Miller, D, Smith, JC, Baudry, J & Quarles, L 2018, 'Computationally identified novel agonists for GPRC6A', PloS one, vol. 13, no. 4, e0195980. https://doi.org/10.1371/journal.pone.0195980
Pi, Min ; Kapoor, Karan ; Ye, Ruisong ; Hwang, Dong Jin ; Miller, Duane ; Smith, Jeremy C. ; Baudry, Jerome ; Quarles, Leigh. / Computationally identified novel agonists for GPRC6A. In: PloS one. 2018 ; Vol. 13, No. 4.
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