Cyclin dependent kinase 5 (CDK5) is a proline directed Ser/Thr kinase, which is expressed primarily in the central nervous system (CNS). CDK5 regulates neuronal development rather than cell division and is deregulated by its neurotoxic activator p25. As a cascade mechanism, tau protein becomes hyperphosphorylated and produces deposits of neurofibrillary tangles (NT). The deregulation of CDK5 is believed to be responsible for several neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, stroke and Huntington's chorea. Because of its involvement in NT formation, the inhibition of CDK5-p25 complex has been identified as a potential therapeutic target for Alzheimer's disease. CDK5 has a high level of structural homology (~60%) with its mitotic counterpart CDK2, which has made it difficult to design selective CDK5 inhibitors. We employed structure based virtual screening of a commercial database containing 2.5 million compounds to identify a group of probable hits. Subsequently, we employed the selectivity constraints from docking scores and identified a limited number of CDK5 selective compounds. These compounds were evaluated in 33P labeled functional assays in order to validate the computational model. A novel, selective and non-ATP competitive CDK5-p25 inhibitor has been identified. The present study highlights the computational model, novel synthetic strategy and further SAR studies of the lead compound.

Identification of novel, selective CDK5/p25 inhibitor: Structure based virtual screening, synthesis, biological evaluation and SAR studies

246th National Meeting (2013)

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