SMARTCyp: A 2D method for prediction of cytochrome P450-mediated drug metabolism

TY - JOUR

T1 - SMARTCyp

T2 - A 2D method for prediction of cytochrome P450-mediated drug metabolism

AU - Rydberg, Patrik

AU - Gloriam, David Erik Immanuel

AU - Zaretzki, Jed

AU - Breneman, Curt

AU - Olsen, Lars

N1 - Keywords: cytochromes P450, metabolism, DFT, density functional theory, heme

PY - 2010/6/10

Y1 - 2010/6/10

N2 - SMARTCyp is an in silico method that predicts the sites of cytochrome P450-mediated metabolism of druglike molecules. The method is foremost a reactivity model, and as such, it shows a preference for predicting sites that are metabolized by the cytochrome P450 3A4 isoform. SMARTCyp predicts the site of metabolism directly from the 2D structure of a molecule, without requiring calculation of electronic properties or generation of 3D structures. This is a major advantage, because it makes SMARTCyp very fast. Other advantages are that experimental data are not a prerequisite to create the model, and it can easily be integrated with other methods to create models for other cytochrome P450 isoforms. Benchmarking tests on a database of 394 3A4 substrates show that SMARTCyp successfully identifies at least one metabolic site in the top two ranked positions 76% of the time. SMARTCyp is available for download at http://www.farma.ku.dk/p450.

AB - SMARTCyp is an in silico method that predicts the sites of cytochrome P450-mediated metabolism of druglike molecules. The method is foremost a reactivity model, and as such, it shows a preference for predicting sites that are metabolized by the cytochrome P450 3A4 isoform. SMARTCyp predicts the site of metabolism directly from the 2D structure of a molecule, without requiring calculation of electronic properties or generation of 3D structures. This is a major advantage, because it makes SMARTCyp very fast. Other advantages are that experimental data are not a prerequisite to create the model, and it can easily be integrated with other methods to create models for other cytochrome P450 isoforms. Benchmarking tests on a database of 394 3A4 substrates show that SMARTCyp successfully identifies at least one metabolic site in the top two ranked positions 76% of the time. SMARTCyp is available for download at http://www.farma.ku.dk/p450.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/ml100016x

DO - 10.1021/ml100016x

M3 - Letter

C2 - 24936230

SN - 1948-5875

VL - 1

SP - 96

EP - 100

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 3

ER -