Novel Structural Features of CDK Inhibition Revealed by an ab Initio Computational Method Combined with Dynamic Simulations

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• 作者：Lucy Heady ; Marivi Fernandez-Serra ; Ricardo L. Mancera ; Sian Joyce ; Ashok R. Venkitaraman ; Emilio Artacho ; Chris-Kriton Skylaris ; Lucio Colombi Ciacchi ; Mike C. Payne
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 24, 2006
• 年：2006
• 卷：49
• 期：17
• 页码：5141 - 5153
• 全文大小：382K
• 年卷期：v.49,no.17(August 24, 2006)
• ISSN：1520-4804

文摘

The rational development of specific inhibitors for the ~500 protein kinases encoded in the human genomeis 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 computationalapproach linear-scalable to molecular interactions involving thousands of atoms, we have investigated thebinding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarizationand dynamic hydrogen bonding effects, so far undetected by crystallography, affect both their activity andselectivity. The effects arise from the specific solvation patterns of water molecules in the ATP bindingpocket or the intermittent formation of hydrogen bonds during the dynamics of CDK/inhibitor interactionsand explain the unexpectedly high potency of certain inhibitors such as 3-(3H-imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 isobserved to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replacedin CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivityof the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysisof biomolecular structures and reveal hitherto unrecognized features of the interaction between protein kinasesand their inhibitors.