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Fragment-Based Discovery of Subtype-Selective Adenosine Receptor Ligands from Homology Models

Ranganathan, Anirudh; Stoddart, Leigh A.; Hill, Stephen J.; Carlsson, Jens

Authors

Anirudh Ranganathan

Leigh A. Stoddart

STEPHEN HILL steve.hill@nottingham.ac.uk
Professor of Molecular Pharmacology

Jens Carlsson



Abstract

Fragment-based lead discovery (FBLD) holds great promise for drug discovery, but applications to G protein-coupled receptors (GPCRs) have been limited by a lack of sensitive screening techniques and scarce structural information. If virtual screening against homology models of GPCRs could be used to identify fragment ligands, FBLD could be extended to numerous important drug targets and contribute to efficient lead generation. Access to models of multiple receptors may further enable the discovery of fragments that bind specifically to the desired target. To investigate these questions, we used molecular docking to screen >500 000 fragments against homology models of the A3 and A1 adenosine receptors (ARs) with the goal to discover A3AR-selective ligands. Twenty-one fragments with predicted A3AR-specific binding were evaluated in live-cell fluorescence-based assays; of eight verified ligands, six displayed A3/A1 selectivity, and three of these had high affinities ranging from 0.1 to 1.3 μM. Subsequently, structure-guided fragment-to-lead optimization led to the identification of a >100-fold-selective antagonist with nanomolar affinity from commercial libraries. These results highlight that molecular docking screening can guide fragment-based discovery of selective ligands even if the structures of both the target and antitarget receptors are unknown. The same approach can be readily extended to a large number of pharmaceutically important targets.

Citation

Ranganathan, A., Stoddart, L. A., Hill, S. J., & Carlsson, J. (2015). Fragment-Based Discovery of Subtype-Selective Adenosine Receptor Ligands from Homology Models. Journal of Medicinal Chemistry, 58(24), 9578-9590. https://doi.org/10.1021/acs.jmedchem.5b01120

Journal Article Type Article
Acceptance Date Nov 22, 2015
Online Publication Date Dec 8, 2015
Publication Date Dec 24, 2015
Deposit Date Jul 18, 2016
Publicly Available Date Jul 18, 2016
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 58
Issue 24
Pages 9578-9590
DOI https://doi.org/10.1021/acs.jmedchem.5b01120
Public URL http://eprints.nottingham.ac.uk/id/eprint/34664
Publisher URL http://dx.doi.org/10.1021/acs.jmedchem.5b01120
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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