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Structure-Based Screening of Uncharted Chemical Space for Atypical Adenosine Receptor Agonists
Stockholm Univ, Sci Life Lab, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden.;Stockholm Univ, Ctr Biomembrane Res, SE-10691 Stockholm, Sweden..
NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA..
NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA..
NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA..
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2016 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 11, no 10, 2763-2772 p.Article in journal (Refereed) Published
Abstract [en]

Small molecule screening libraries cover only a small fraction of the astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for inflammation and cardiovascular diseases has been hampered by the paucity of agonist scaffolds. To identify novel AR agonists, a virtual library of synthetically tractable nucleosides with alternative bases was generated and structure-based virtual screening guided selection of compounds for synthesis. Pharmacological assays were carried out at three AR subtypes for 13 ribosides. Nine compounds displayed significant activity at the ARs, and several of these represented atypical agonist scaffolds. The discovered ligands also provided insights into receptor activation and revealed unknown interactions of endogenous and clinical compounds with the ARs. The results demonstrate that virtual compound databases provide access to bioactive matter from regions of chemical space that are sparsely populated in commercial libraries, an approach transferrable to numerous drug targets.

Place, publisher, year, edition, pages
2016. Vol. 11, no 10, 2763-2772 p.
National Category
Medicinal Chemistry
URN: urn:nbn:se:uu:diva-311521DOI: 10.1021/acschembio.6b00357ISI: 000386187700012PubMedID: 27439119OAI: oai:DiVA.org:uu-311521DiVA: diva2:1060329
Swedish Research Council, 2013-05708Swedish Foundation for Strategic Research , ICA10-0098Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2016-12-28 Created: 2016-12-28 Last updated: 2016-12-28Bibliographically approved

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Carlsson, Jens
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Science for Life Laboratory, SciLifeLabDepartment of Medicinal Chemistry
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