TY - JOUR

T1 - Fast prediction of cytochrome P450 mediated drug metabolism

AU - Rydberg, Patrik Åke Anders

AU - Poongavanam, Vasanthanathan

AU - Oostenbrink, Chris

AU - Olsen, Lars

PY - 2009

Y1 - 2009

N2 - Cytochrome P450 mediated metabolism of drugs is one of the major determinants of their kinetic profile, and prediction of this metabolism is therefore highly relevant during the drug discovery and development process. A new rule-based method, based on results from density functional theory calculations, for predicting activation energies for aliphatic and aromatic oxidations by cytochromes P450 is developed and compared with several other methods. Although the applicability of the method is currently limited to a subset of P450 reactions, these reactions describe more than 90 % of the metabolites. The rules employed are relatively few and general, and when combined with solvent-accessible surface area calculations to account for steric accessibility, the method gives a major P450 metabolite as first-ranked position for 75 % of the substrates, and ranked in the top three for 90 % of substrates for a set of 20 substrates. In combination with docking, it can predict isoform-specific metabolism, and we apply this on CYP1A2 with very good results on 81 substrates, for which we find a major metabolite ranked in the top three for 90 % of the substrates (100 % in the training set and 87 % in the larger test set).

AB - Cytochrome P450 mediated metabolism of drugs is one of the major determinants of their kinetic profile, and prediction of this metabolism is therefore highly relevant during the drug discovery and development process. A new rule-based method, based on results from density functional theory calculations, for predicting activation energies for aliphatic and aromatic oxidations by cytochromes P450 is developed and compared with several other methods. Although the applicability of the method is currently limited to a subset of P450 reactions, these reactions describe more than 90 % of the metabolites. The rules employed are relatively few and general, and when combined with solvent-accessible surface area calculations to account for steric accessibility, the method gives a major P450 metabolite as first-ranked position for 75 % of the substrates, and ranked in the top three for 90 % of substrates for a set of 20 substrates. In combination with docking, it can predict isoform-specific metabolism, and we apply this on CYP1A2 with very good results on 81 substrates, for which we find a major metabolite ranked in the top three for 90 % of the substrates (100 % in the training set and 87 % in the larger test set).

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1002/cmdc.200900363

DO - 10.1002/cmdc.200900363

M3 - Journal article

C2 - 19852016

VL - 4

SP - 2070

EP - 2079

JO - Farmaco

JF - Farmaco

SN - 1860-7179

IS - 12

ER -