Abstract
Cyclin-dependent kinases (CDKs) belong to the CMGC subfamily of protein kinases and play crucial roles in eukaryotic cell division cycle. At least seven different CDKs have been reported to be implicated in the cell cycle regulation in vertebrates. These CDKs are highly homologous and contain a conserved catalytic core. This makes the design of inhibitors specific for a particular CDK difficult. There is, however, growing need for CDK5 specific inhibitors to treat various neurodegenerative diseases. Recently, cis-substituted cyclobutyl-4-aminoimidazole inhibitors have been identified as potent CDK5 inhibitors that gave up to 30-fold selectivity over CDK2. Available IC50 values also indicate a higher potency of this class of inhibitors over commercially available drugs, such as roscovitine. To understand the molecular basis of higher potency and selectivity of these inhibitors, here, we present molecular dynamics simulation results of CDK5/p25 and CDK2/CyclinE complexed with a series of cyclobutyl-substituted imidazole inhibitors and roscovitine. The atomic details of the stereospecificity and selectivity of these inhibitors are obtained from energetics and binding characteristics to the CDK binding pocket. The study not only complements the experimental findings, but also provides a wealth of detailed information that could help the structure-based drug designing processes.
Highlights
Cyclin-dependent kinases (CDKs) play crucial roles in eukaryotic cell division cycle
As the kinase inhibition assay was performed in active complexes, the CDK-inhibitor interactions were examined in presence of the activators, cyclin E and p25 for CDK2 and CDK5, respectively
Binding of cis- and trans-OH to Active CDK2 and CDK5 To test the stability of the systems, we monitored the root mean squared deviations (RMSD) of the inhibitor-bound CDK complexes from the starting structures
Summary
Cyclin-dependent kinases (CDKs) play crucial roles in eukaryotic cell division cycle. They belong to the CMGC subfamily of protein kinases and assist the c-phosphate transfer from ATP to peptide substrates [1], [2]. CDK2, like most of the other CDKs, follows a two-step process to become fully functional: (i) the association with the regulatory subunit – cyclin A or cyclin E, (ii) phosphorylation of residue Thr160 located in the so-called activation loop [5], [6]. The activity of CDK5 is restricted to nervous system by the localization of its activators p25/p35/p39, the binding of which makes CDK5 fully active without the subsequent requirement of phosphorylation of the activation loop residue [7], [8]. While aberrant activity of CDK2 has been identified in a number of diseases including cancer, embryonic lethality, male sterility etc., the deregulation of CDK5 causes serious neurodegenerative disorders, e.g. Alzheimer’s disease, lateral sclerosis, stroke etc [9,10,11]
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