title: Study of the inhibition of cyclin-dependent kinases with roscovitine and indirubin-3'-oxime from molecular dynamics simulations.
abstract: Molecular dynamics simulations were performed to elucidate the interactions of CDK2 and CDK5 complexes with three inhibitors: R-roscovitine, S-roscovitine, and indirubin-3'-oxime. The preference of the two complexes for R-roscovitine over the S enantiomer, as reported by the experiment, was also found by the simulations. More importantly, the simulations showed that the cause of the stronger affinity for the R enantiomer is the presence of an important hydrogen bond between R-roscovitine and the kinases not found with S-roscovitine. The simulations also showed two amino acid mutations in the active site of CDK5/R-roscovitine that favor binding-enhanced electrostatic contributions, making the inhibitor more effective for CDK5 than for CDK2. This suggests that the effectiveness of roscovitine-like inhibitors can be improved by enhancing their electrostatic interaction with the kinases. Finally, molecular mechanics-Possion-Boltzmann/surface area calculations of the CDK5/indirubin-3'-oxime system in both water-excluded and water-included environments gave significantly different electrostatic contributions to the binding. The simulations detected the displacement of a water molecule in the active site of the water-included CDK/indirubin-3'-oxime system. This resulted in a more conserved binding pattern than the water-excluded structure. Hence, in the design of new indirubin-like inhibitors, it is important to include the water molecule in the analysis.
authors.affiliation: Nanoscience and Nanotechnology Initiative, National University of Singapore, 2 Engineering Drive 3, Singapore, 117576, Singapore.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Vincent B C
authors.initials: VB
authors.lastname: Tan
authors.forename: Kian Meng
authors.initials: KM
authors.lastname: Lim
authors.forename: Tong Earn
authors.initials: TE
authors.lastname: Tay
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018844:Cyclin-Dependent Kinases / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D010091:Oximes / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D012984:Software; D055672:Static Electricity; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011687:Purines; C474021:indirubin-3'-monoxime; D014867:Water; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases