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Fragment-Based Discovery of Subtype-Selective Adenosine Receptor Ligands from Homology Models
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
2015 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 58, no 24, 9578-9590 p.Article in journal (Refereed) PublishedText
Abstract [en]

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 A(3) and A(1) adenosine receptors (ARs) with the goal to discover,A(3)AR-selective ligands. Twenty-one fragments with predicted A(3)AR-specific binding were evaluated in live-cell fluorescence-based assays; of eight verified ligands, six displayed A(3)/A(1), selectivity,, and three of these had high affinities ranging from 0.1 to 1.3 mu M. 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.

Place, publisher, year, edition, pages
2015. Vol. 58, no 24, 9578-9590 p.
National Category
Medicinal Chemistry Biochemistry and Molecular Biology Theoretical Chemistry
URN: urn:nbn:se:uu:diva-269376DOI: 10.1021/acs.jmedchem.5b01120ISI: 000367563100011PubMedID: 26592528OAI: oai:DiVA.org:uu-269376DiVA: diva2:882870
Knut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Swedish Research Council
Available from: 2015-12-15 Created: 2015-12-15 Last updated: 2016-02-02Bibliographically approved

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