CYP 2D6 binding affinity predictions using multiple ligand and protein conformations

Int J Mol Sci. 2013 Dec 17;14(12):24514-30. doi: 10.3390/ijms141224514.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytochrome P-450 CYP2D6 / chemistry
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Ligands*
  • Models, Molecular*
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Thermodynamics
  • Thiourea / chemistry
  • Thiourea / metabolism


  • Ligands
  • Cytochrome P-450 CYP2D6
  • Thiourea