Comparative docking to distinct G protein-coupled receptor conformations exclusively yields ligands with agonist efficacy.

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2019
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Abstract
G protein-coupled receptors exist in a whole spectrum of conformations which are stabilised by the binding of ligands with different efficacy or intracellular effector proteins. Here, we investigate whether three-dimensional structures of receptor conformations in different states of activation can be utilised to enrich ligands with agonist behaviour in prospective docking calculations. We focused on the β-adrenergic receptor, as it currently is the receptor with the highest number of active-state crystal structures. Comparative docking calculations to distinct conformations of the receptor were used for the prediction of ligands with agonist efficacy. The pharmacology of molecules selected based on these predictions was characterised experimentally, resulting in a hit rate of 37% ligands, all of which were agonists. The ligands furthermore contain a pyrazole moiety which has previously not been described for β -adrenergic receptor ligands and one of them shows an intrinsic efficacy comparable to salbutamol. SIGNIFICANCE STATEMENT: Structure-based ligand design for G protein-coupled receptors crucially depends on receptor conformation and hence their activation state. We explored the influence of using multiple active-conformation X-ray structures on the hit rate of docking calculations to find novel agonists and how to predict the most fruitful strategy to apply. The results suggest that aggregating the ranks of molecules across docking calculations to more than one active-state structure exclusively yields agonists.
Reference Key
scharf2019comparativemolecular Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Scharf, Magdalena Martina;Bunemann, Moritz;Baker, Jillian Glenda;Kolb, Peter;
Journal molecular pharmacology
Year 2019
DOI
mol.119.117515
URL
Keywords
molecular modeling drug development g protein-coupled receptors (gpcrs) ligand docking adrenergic receptors beta-adrenergic receptors computational drug design high throughput screening receptor structure

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