Abstract
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 Q2 > 0.63 and Q2 > 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.
Highlights
The glucagon receptor subfamily of secretin-like G protein-coupled receptors includesGCGR, GLP-1R, and GIPR
That small-molecule compounds may act as negative allosteric modulators when bound to the extra-helical region of transmembrane domains (TMDs) [5,7]
There had been no complexes with small-molecule ligands targeting orthosteric sites of class B GPCRs described by either X-ray crystallography or cryogenic-electron microscopy (cryo-EM) and it was not clear how smallmolecule agonists could interact with TMD [10,11]
Summary
The glucagon receptor subfamily of secretin-like G protein-coupled receptors includesGCGR, GLP-1R (and GLP-2R), and GIPR. A physiological model of their activation involves peptide agonists: glucagon, GLP-1, GLP-2, and GIP and is involved in G protein-mediated signal transduction that leads to an increase or decrease in glucose/insulin blood serum levels [1,2]. Drug discovery for the glucagon receptor family succeeded in more potent analogs of endogenous peptides targeting the orthosteric binding site and small-molecule ligands targeting the extra-helical, allosteric sites of these receptors [2,4]. The later ones, with a V-shaped conformation, block transmembrane helix 6 (TMH6) deformation and prevent receptor activation. They act as negative allosteric modulators (NAMs), which binding modes has been discovered only recently [5,6,7]. Non-peptide agonists of the glucagon receptor subfamily members were known, e.g., Boc or BETP, it was not clear how they could interact with transmembrane domains (TMDs) [8,9]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call