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

Lucy Heady,^† Marivi Fernandez-Serra,^‡ Ricardo L. Mancera,^§ Sian Joyce,^† Ashok R. Venkitaraman, Emilio Artacho,^# Chris-Kriton Skylaris, Lucio Colombi Ciacchi,*^† and Mike C. Payne^†

Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, J. J. Thomson Avenue, Cambridge CB3 0HE, U.K., Dpartment de Physique des Matriaux, Universit Claude Bernard Lyon, 69622 Villeurbanne, France, Western Australian Biomedical Research Institute & School of Pharmacy, and School of Biomedical Sciences, Curtin University of Technology, GPO Box U1987, Perth WA 6845, Australia, Photonics Theory Group, Tyndall National Institute, Lee Maltings, Cork, Ireland, CR UK Department of Oncology & The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, U.K., Earth Sciences Department, University of Cambridge, Cambridge CB2 3EQ, U.K., School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, U.K., and Fraunhofer Institut fr Werkstoffmechanik, Whlerstrasse 11, 79108 Freiburg, Germany

J. Med. Chem., 2006, 49 (17), pp 5141–5153

DOI: 10.1021/jm060190+

Publication Date (Web): August 3, 2006

†

Theory of Condensed Matter Group, University of Cambridge.

‡

Université Claude Bernard Lyon.

Curtin University of Technology.

Tyndall National Institute.

Hutchison/MRC Research Centre.

Earth Sciences Department, University of Cambridge.

University of Southampton.

To whom correspondence should be addressed. Tel: +49 761 5142113. Fax: +49 761 5142404. E-mail: lucio@izbs.uni-karlsruhe.de.

Fraunhofer Institut für Werkstoffmechanik.

Abstract

The rational development of specific inhibitors for the 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 molecules that 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-(3H-imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors.