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.
Keywords: Adenosine kinase inhibitors; ROC; epilepsy; molecular dynamics; quantum mechanics; structure-based virtual screening.