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- Title
Molecular dynamics simulations on the inhibition of Cyclin-Dependent Kinases 2 and 5 in the presence of activators.
- Authors
Zhang, Bing; Tan, Vincent B. C.; Lim, Kian Meng; Tay, Tong Earn
- Abstract
Interests in CDK2 and CDK5 have stemmed mainly from their association with cancer and neuronal migration or differentiation related diseases and the need to design selective inhibitors for these kinases. Molecular dynamics (MD) simulations have not only become a viable approach to drug design because of advances in computer technology but are increasingly an integral part of drug discovery processes. It is common in MD simulations of inhibitor/CDK complexes to exclude the activator of the CDKs in the structural models to keep computational time tractable. In this paper, we present simulation results of CDK2 and CDK5 with roscovitine using models with and without their activators (cyclinA and p25). While p25 was found to induce slight changes in CDK5, the calculations support that cyclinA leads to significant conformational changes near the active site of CDK2. This suggests that detailed and structure-based inhibitor design targeted at these CDKs should employ activator-included models of the kinases. Comparisons between P/CDK2/cyclinA/roscovitine and CDK5/p25/roscovitine complexes reveal differences in the conformations of the glutamine around the active sites, which may be exploited to find highly selective inhibitors with respect to CDK2 and CDK5.
- Subjects
CYCLIN-dependent kinases; DRUG design; MOLECULAR dynamics; PROTEIN kinases; NEURODEGENERATION; CANCER; COMPUTER engineering
- Publication
Journal of Computer-Aided Molecular Design, 2006, Vol 20, Issue 6, p395
- ISSN
0920-654X
- Publication type
Article
- DOI
10.1007/s10822-006-9081-z