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2006
Journal Article
Titel
Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations
Abstract
The rational development of specific inhibitors for 500 protein kinases encoded in the human genome is impeded by a poor understanding of the structural basis for the activity and selectivity of small moleculesthat compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects, so far undetected by crystallography, affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK/inhibitor interactions and explain the unexpectedly high potency of certain inhibitors such as 3-5 methoxy-1,3-dihydro-indol-2-one.
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