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The large amount of data that has been collected so far for G protein-coupled receptors requires machine learning (ML) approaches to fully exploit its potential. Our previous ML model based on gradient boosting used for prediction of drug affinity and selectivity for a receptor subtype was compared with explicit information on ligand-receptor interactions from induced-fit docking. Both methods have proved their usefulness in drug response predictions. Yet, their successful combination still requires allosteric/orthosteric assignment of ligands from datasets. Our ligand datasets included activities of two members of the secretin receptor family: GCGR and GLP-1R. Simultaneous activation of two or three receptors of this family by dual or triple agonists is not a typical kind of information included in compound databases. A precise allosteric/orthosteric ligand assignment requires a continuous update based on new structural and biological data. This data incompleteness remains the main obstacle for current ML methods applied to class B GPCR drug discovery. Even so, for these two class B receptors, our ligand-based ML model demonstrated high accuracy (5-fold cross-validation Q > 0.63 and Q > 0.67 for GLP-1R and GCGR, respectively). In addition, we performed a ligand annotation using recent cryogenic-electron microscopy (cryo-EM) and X-ray crystallographic data on small-molecule complexes of GCGR and GLP-1R. As a result, we assigned GLP-1R and GCGR actives deposited in ChEMBL to four small-molecule binding sites occupied by positive and negative allosteric modulators and a full agonist. Annotated compounds were added to our recently released repository of GPCR data.
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http://dx.doi.org/10.3390/ijms22084060 | DOI Listing |
Nat Commun
November 2024
Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications. Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/glucagon-like peptide-1 receptor (GCGR/GLP-1R) agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas, and liver which is initiated by a rapid release of free fatty acids (FFAs) by white adipose tissue (WAT) in a GCGR-dependent manner. This interactome leads to elevations in adiponectin and fibroblast growth factor 21 (FGF21), causing WAT beiging, brown adipose tissue (BAT) activation, increased energy expenditure (EE) and weight loss.
View Article and Find Full Text PDFDiabetol Metab Syndr
November 2024
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, 6-151 61 Queen Street East, Toronto, ON, M5C 2T2, Canada.
Background: Several new treatments have recently been shown to have heart and kidney protective benefits in people with diabetes. Because these treatments were developed in parallel, it is unclear how the different molecular pathways affected by the therapies may overlap. Here, we examined the effects of the mineralocorticoid receptor antagonist finerenone in mice with comorbid diabetes, focusing on the regulation of expression of the glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor (GIPR) and glucagon receptor (GCGR), which are targets of approved or investigational therapies in diabetes.
View Article and Find Full Text PDFJ Endocr Soc
October 2024
Department of Internal Medicine, Endocrinology, Diabetes and Metabolism Unit, University of Rwanda, Kigali 00200, Rwanda.
Cell Biosci
August 2024
Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, China.
Background: Arginine vasopressin (AVP) has been reported to regulate insulin secretion and glucose homeostasis in the body. Previous study has shown that AVP and its receptor V1bR modulate insulin secretion via the hypothalamic-pituitary-adrenal axis. AVP has also been shown to enhance insulin secretion in islets, but the exact mechanism remains unclear.
View Article and Find Full Text PDFBiochem Pharmacol
November 2024
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia; ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia. Electronic address:
Class B1 G protein-coupled receptors (GPCRs) are peptide hormone receptors and well validated therapeutic targets, however development of non-peptide drugs targeting this class of receptors is challenging. Recently, a series of isoquinoline-based derivates were reported in the patent literature as allosteric ligands for the glucagon receptor subfamily, and two compounds, LSN3451217 and LSN3556672, were used to facilitate structural studies with the glucagon-like peptide-1 receptor (GLP-1R) and glucose dependent insulinotropic peptide receptor (GIPR) bound to orthosteric agonists. Here we pharmacologically characterized stereoisomers of LSN3451217 and LSN3556672, across the class B1 GPCR family.
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