title: An in silico approach for the discovery of CDK5/p25 interaction inhibitors.
abstract: The lack of selectivity of all existing ATP competitive inhibitors for a single cyclin-dependent kinase (CDK) has led us to redirect the structure-based molecule design from targeting the classic ATP-binding pocket in CDK5 toward the CDK5/p25 interface. The aim was to seek novel inhibition mechanisms to interrupt protein-protein interactions. A combined strategy of alanine-scanning calculations for locating binding sites, virtual screening for small molecules, molecular dynamics simulations for examining the binding stability of virtual screening hits and bio-assays for testing the level of inhibition was set up and used to explore novel inhibitors capable of interrupting the interactions between the proteins, and consequently of inhibiting the kinase activity. Two compounds were shown to inhibit the complex formation between CDK5 and p25 through p25 binding. They could open avenues for the discovery of new types of structures that prevent interactions between CDK5 and p25 or other CDK and activator proteins, and, more importantly, provide leads in the development of selective inhibitors among CDKs.
authors.affiliation: Thermal Physics Center, School of Renewable Energy, North China Electric Power University, Beijing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Caroline
authors.initials: C
authors.lastname: Corbel
authors.forename: Françoise
authors.initials: F
authors.lastname: Guéritte
authors.forename: Cyril
authors.initials: C
authors.lastname: Couturier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bach
authors.forename: Vincent B C
authors.initials: VB
authors.lastname: Tan
mesh_terms: D019925:Cyclin A / Q000737:chemistry / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D015203:Reproducibility of Results
chemical_list: D019925:Cyclin A; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5