Magdalena M. Scharf
Comparative Docking to Distinct G Protein–Coupled Receptor Conformations Exclusively Yields Ligands with Agonist Efficacy
Scharf, Magdalena M.; B�nemann, Moritz; Baker, Jillian G.; Kolb, Peter
Authors
Moritz B�nemann
JILLIAN BAKER jillian.baker@nottingham.ac.uk
Professor of Drug Discovery and Respiratory Medicine
Peter Kolb
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 ?2-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 in silico 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 ?2 -adrenergic receptor ligands and one of them shows an intrinsic efficacy comparable to salbutamol.
Citation
Scharf, M. M., Bünemann, M., Baker, J. G., & Kolb, P. (2019). Comparative Docking to Distinct G Protein–Coupled Receptor Conformations Exclusively Yields Ligands with Agonist Efficacy. Molecular Pharmacology, 96(6), 851-861. https://doi.org/10.1124/mol.119.117515
Journal Article Type | Article |
---|---|
Acceptance Date | Oct 17, 2019 |
Online Publication Date | Oct 17, 2019 |
Publication Date | 2019-12 |
Deposit Date | Nov 19, 2019 |
Publicly Available Date | Nov 19, 2019 |
Journal | Molecular Pharmacology |
Print ISSN | 0026-895X |
Electronic ISSN | 1521-0111 |
Publisher | American Society for Pharmacology and Experimental Therapeutics |
Peer Reviewed | Peer Reviewed |
Volume | 96 |
Issue | 6 |
Pages | 851-861 |
DOI | https://doi.org/10.1124/mol.119.117515 |
Keywords | Molecular Medicine; Pharmacology |
Public URL | https://nottingham-repository.worktribe.com/output/3331208 |
Publisher URL | http://molpharm.aspetjournals.org/content/early/2019/10/17/mol.119.117515 |
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