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ACS Chem Biol. 2016 Oct 21;11(10):2763-2772. Epub 2016 Aug 22.

Structure-Based Screening of Uncharted Chemical Space for Atypical Adenosine Receptor Agonists.

Author information

Science for Life Laboratory, Department of Biochemistry and Biophysics and Center for Biomembrane Research, Stockholm University , SE-106 91 Stockholm, Sweden.
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
Science for Life Laboratory, Department of Medicinal Chemistry, BMC, Uppsala University , P.O. Box 574, SE-751 23 Uppsala, Sweden.


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.

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