Cyclin Dependent Kinase 5 (CDK5) is currently an attractive target in Alzheimer’s disease research, thanks to its key role in Tau protein hyperphosphorylation. Ca2+ homeostasis disruption activates calpain enzyme cleaving the physiological CDK5 activator, p35, to its truncated form, p25, which has about 7-10 times longer half-life. CDK5/P25 interaction causes CDK5 hyperactivation leading to the neurofibrillary tangles formation which is one of Alzheimer’s disease hallmarks. Trials to inhibit whether the kinase activity of CDK5 by directly targeting its ATP binding site or the protein-protein (CDK5/P25) interaction were not successful owing to the obvious lack of selectivity of those inhibitors. In our search for other non-classical approaches, exploring p35 revealed a novel possible druggable site proximate calpain binding site. The aim of the current research phase is to design indirect calpain inhibitors interfering with its binding to p35 utilizing this revealed binding site.
Ahmed intends to achieve the following milestones:
- De-novo design of indirect small molecule calpain-p35 binding inhibitors.
- Docking of those compounds and validating their predicted effect through running molecular dynamics simulation to the best lead compounds.
- Devising synthetic scheme to the best selected compounds.