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Title: Study of the inhibition of cyclin-dependent kinases with roscovitine and indirubin-3′-oxime from molecular dynamics simulations
Authors: Zhang, B. 
Tan, V.B.C. 
Lim, K.M. 
Tay, T.E. 
Zhuang, S.
Keywords: Binding energy
Binding pattern
Cycline-dependent kinase
Hydrogen bond
Molecular dynamics simulation
Issue Date: Jan-2007
Citation: Zhang, B., Tan, V.B.C., Lim, K.M., Tay, T.E., Zhuang, S. (2007-01). Study of the inhibition of cyclin-dependent kinases with roscovitine and indirubin-3′-oxime from molecular dynamics simulations. Journal of Molecular Modeling 13 (1) : 79-89. ScholarBank@NUS Repository.
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. © Springer-Verlag 2006.
Source Title: Journal of Molecular Modeling
ISSN: 16102940
DOI: 10.1007/s00894-006-0127-x
Appears in Collections:Staff Publications

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