A categorical structure-activity relationship analysis of GPR119 ligands.

نویسندگان

  • Pritesh Kumar
  • Carl A Carrasquer
  • Arren Carter
  • Zhao-Hui Song
  • Albert R Cunningham
چکیده

The categorical structure-activity relationship (cat-SAR) expert system has been successfully used in the analysis of chemical compounds that cause toxicity. Herein we describe the use of this fragment-based approach to model ligands for the G protein-coupled receptor 119 (GPR119). Using compounds that are known GPR119 agonists and compounds that we have confirmed experimentally that are not GPR119 agonists, four distinct cat-SAR models were developed. Using a leave-one-out validation routine, the best GPR119 model had an overall concordance of 99%, a sensitivity of 99%, and a specificity of 100%. Our findings from the in-depth fragment analysis of several known GPR119 agonists were consistent with previously reported GPR119 structure-activity relationship (SAR) analyses. Overall, while our results indicate that we have developed a highly predictive cat-SAR model that can be potentially used to rapidly screen for prospective GPR119 ligands, the applicability domain must be taken into consideration. Moreover, our study demonstrates for the first time that the cat-SAR expert system can be used to model G protein-coupled receptor ligands, many of which are important therapeutic agents.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Mutation-Guided Unbiased Modeling of the Fat Sensor GPR119 for High-Yield Agonist Screening.

Recent benchmark studies have demonstrated the difficulties in obtaining accurate predictions of ligand binding conformations to comparative models of G-protein-coupled receptors. We have developed a data-driven optimization protocol, which integrates mutational data and structural information from multiple X-ray receptor structures in combination with a fully flexible ligand docking protocol t...

متن کامل

Lipid derivatives activate GPR119 and trigger GLP-1 secretion in primary murine L-cells

AIMS/HYPOTHESIS Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from proglucagon, which is released from intestinal L-cells and increases insulin secretion in a glucose dependent manner. GPR119 is a lipid derivative receptor present in L-cells, believed to play a role in the detection of dietary fat. This study aimed to characterize the responses of primary murine L-cells to GPR1...

متن کامل

A GPR119 Signaling System in the Murine Eye Regulates Intraocular Pressure in a Sex-Dependent Manner

Purpose GPR119 is a G protein-coupled receptor that may be the endogenous target for 2-oleoylglycerol (2-OG), a lipid related to the endocannabinoid family of neuromodulators. Interest in GPR119 has centered on its role in regulating insulin secretion; however, the role of GPR119 has not been examined in the eye. The purpose of this study was to explore a potential GPR119-based signaling system...

متن کامل

Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells

BACKGROUND AND PURPOSE GPR119 is a G protein-coupled receptor that is preferentially expressed in islet cells and mediates insulin secretion. Oleoyl-lysophosphatidylcholine and oleoylethanolamide (OEA) act as endogenous ligands for this receptor, whereas PSN375963 and PSN632408 are two recently reported synthetic agonists. In this study, we explored mechanisms underlying GPR119-induced insulin ...

متن کامل

Biased signaling of lipids and allosteric actions of synthetic molecules for GPR119.

GPR119 is a Gαs-coupled lipid-sensor in the gut, where it mediates release of incretin hormones from the enteroendocrine cells and in pancreatic α-cells, where it releases insulin. Naturally occurring lipids such as monoacylglycerols (MAGs) and N-acylethanolamines (NAEs), like oleoylethanolamide (OEA), activate GPR119, and multiple synthetic ligands have been described. Here, we extend the GPR1...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • SAR and QSAR in environmental research

دوره 25 11  شماره 

صفحات  -

تاریخ انتشار 2014