Ligand-Based Site of Metabolism Prediction for Cytochrome P450 2D6

Patrik Rydberg; Lars Olsen

doi:10.1021/ml200246f

Ligand-Based Site of Metabolism Prediction for Cytochrome P450 2D6

ACS Med Chem Lett. 2011 Nov 7;3(1):69-73. doi: 10.1021/ml200246f. eCollection 2012 Jan 12.

Authors

Patrik Rydberg¹, Lars Olsen¹

Affiliation

¹ Biostructural Research, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.

Abstract

A ligand-based method based on the SMARTCyp approach that predicts the sites of cytochrome P450 2D6-mediated metabolism of druglike molecules has been developed. The method uses only two descriptors besides the reactivity from SMARTCyp: the distance to a protonated nitrogen atom and the distance to the end of the molecule. Hence, the site of metabolism is predicted directly from the 2D structure of a molecule, without requiring calculation of electronic properties or generation of 3D structures. Testing on an independent test set gives an area under the curve value of 0.94, and a site of metabolism is found among the top two ranked atoms for 91% of the compounds.

Keywords: CYP2D6; cytochrome P450; drug metabolism.