Molecular basis of differential selectivity of cyclobutyl-substituted imidazole inhibitors against CDKs: insights for rational drug design.
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.
Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.
Soumya Lipsa
SL
Rath
Sanjib
S
Senapati
D000818:Animals; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000737:chemistry*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011687:Purines / Q000737:chemistry; D000077546:Roscovitine; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D019927:Cyclin E; D007093:Imidazoles; D008024:Ligands; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; C118136:TPPP protein, human; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5; C495894:CDK2 protein, human; C495905:CDK5 protein, human; D051357:Cyclin-Dependent Kinase 2