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Biophys. J. BioFAST: First Published November 3, 2006. doi:10.1529/biophysj.106.091512
© 2006 by the Biophysical Society.

A more recent version of this article appeared on January 15, 2007.
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BIOPHYSICAL THEORY AND MODELING

A Computational Study of the Protein-Ligand Interactions in CDK2 Inhibitors: Using QM/MM Interaction Energy as a Predictor of the Biological Activity

Jans H. Alzate-Morales 1*, Renato Contreras 1, Alejandro Soriano 2, Iñaki Tuñon 2 and Estanislao Silla 2

1 Universidad de Chile
2 Universidad de Valencia

* To whom correspondence should be addressed. E-mail: jalzate{at}ciq.uchile.cl.

Submitted on June 20, 2006
Revised on August 17, 2006
Accepted on 6 October 2006


  Abstract
We report a combined quantum mechanics /molecular mechanics (QM/MM) study to determine the protein-ligand interaction energy between CDK2 (Cyclin-Dependent Kinase 2) and five inhibitors with the N2-substituted 6-cyclohexylmethoxypurine scaffold. The present computational results show that the QM/MM interaction energy is strongly correlated to the biological activity and can be used as a predictor, at least within a family of substrates. A detailed analysis of the protein-ligand structures obtained from molecular dynamics simulations shows specific interactions within the active site that, in some cases, have not been reported before. The computed interaction energy gauges the strength of protein-ligand interactions. Finally, energy decomposition and multiple regression analyses were performed to check the contribution of the electrostatic and van der Waals energies to the total interaction energy; and to show the capabilities of the computational model to identify new potent inhibitors.

Key Words: ATP competitive inhibitors, CDK2, SAR, cancer, computational hybrid methods




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[Abstract] [Full Text] [PDF]


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Copyright © 2006 by the Biophysical Society.