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Int. J. Mol. Sci. 2013, 14(12), 24514-24530; doi:10.3390/ijms141224514

CYP 2D6 Binding Affinity Predictions Using Multiple Ligand and Protein Conformations

1
AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
2
Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Muthgasse 18, 1190 Vienna, Austria
Deceased on 18 December 2011.
*
Author to whom correspondence should be addressed.
Received: 1 November 2013 / Revised: 28 November 2013 / Accepted: 4 December 2013 / Published: 17 December 2013
(This article belongs to the Special Issue Xenobiotic Metabolism)
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Abstract

Because of the large flexibility and malleability of Cytochrome P450 enzymes (CYPs), in silico prediction of CYP binding affinities to drugs and other xenobiotic compounds is a true challenge. In the current work, we use an iterative linear interaction energy (LIE) approach to compute CYP binding affinities from molecular dynamics (MD) simulation. In order to improve sampling of conformational space, we combine results from simulations starting with different relevant protein-ligand geometries. For calculated binding free energies of a set of thiourea compounds binding to the flexible CYP 2D6 isoform, improved correlation with experiment was obtained by combining results of MD runs starting from distinct protein conformations and ligand-binding orientations. This accuracy was obtained from relatively short MD simulations, which makes our approach computationally attractive for automated calculations of ligand-binding affinities to flexible proteins such as CYPs.
Keywords: binding free energies; LIE method; CYP 2D6; thiourea ligands binding free energies; LIE method; CYP 2D6; thiourea ligands
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MDPI and ACS Style

Perić-Hassler, L.; Stjernschantz, E.; Oostenbrink, C.; Geerke, D.P. CYP 2D6 Binding Affinity Predictions Using Multiple Ligand and Protein Conformations. Int. J. Mol. Sci. 2013, 14, 24514-24530.

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