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Adenosine kinase (AdK) is a key player in controlling intra- and extracellular concentrations of the signaling molecule adenosine. Extensive evidence points to an important role of AdK in several diseases, and suggests that AdK inhibition might be a promising therapeutic strategy. The development of a new AdK assay and subsequent screening of part of our focused compound library led to the identification of 12 hit compounds (hit rate of 6%) representing six new classes of non-nucleoside human AdK inhibitors. The most potent inhibitor 1 displayed a K i value of 184 nM. Compound screening with a newly developed assay was useful and efficient for discovering novel AdK inhibitors which may serve as lead structures for developing drugs for adenosine augmentation therapy. [ABSTRACT FROM AUTHOR]

Abstract: The structural requirements of pyrrolo[2,3-d]pyrimidine nucleoside (PPN) analogues as adenosine kinase (AK) inhibitors were in silico studied by using CoMSIA method. All models were trained with 32 compounds, after which they were evaluated for predictive ability with additional 5 compounds. Quantitative information on structure–activity trends is provided for further rational development and direction of selective synthesis. The best CoMSIA model included hydrophobic, H-bond donor and H-bond acceptor fields and had a good predictive quality according to internal validation criteria. In addition, this model predicted adequately the compounds contained in the test set. The analysis of the model gives a comprehensive qualitative and quantitative description of the molecular features at C4 and C5 positions of the pyrrolo[2,3-d]pyrimidine scaffold and C5-position of the β-d-ribofuranose of PPN analogues, relevant for a high AK inhibitory activity. [Copyright &y& Elsevier]

The seizure controlling activity of human adenosine kinase (AK) has been identified as a promising target for the development of small-molecule inhibitors to be used as potential anti-epileptic agents. Overexpression of AK has been considered as a pathologic hallmark of epilepsy. However, the exploration of AK for the treatment of epilepsy still remains a challenge in drug discovery. In a pursuit to recognize novel inhibitors of AK, a structure-based virtual screening study based on the molecular docking analysis of the compounds of Asinex database was performed. Crystal structure of human AK in complex with inhibitor revealed the crucial ligand-protein interactions (Asn14, Asn18, Ser65 and Phe170) within the active site and offers opportunities for further development of the potential anti-epileptic agents. Overall, 20 novel diverse potential hits appear to be important scaffolds for the design of novel AK inhibitors with better docking scores, dG bind scores with in silico desired pharmacokinetic parameters and synthetic accessibility scores than the co-crystallized ligand. Computational hits obtained through validated virtual screening protocol (superposition and enrichment) followed by simulation studies, quantum mechanics with better pharmacokinetic performance and hit optimization study provides in silico evidence for the applicability of these valuable tools in drug discovery and towards the development of a better therapeutic regime of epilepsy.Communicated by Ramaswamy H. Sarma.