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. 2010 Mar 15;1(3):96-100.
doi: 10.1021/ml100016x. eCollection 2010 Jun 10.

SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug Metabolism

Patrik Rydberg  1 , David E Gloriam  1 , Jed Zaretzki  2 , Curt Breneman  2 , Lars Olsen  1
Affiliations

SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug Metabolism

Patrik Rydberg et al. ACS Med Chem Lett. .

Abstract

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.

Keywords: Cytochromes P450; DFT; density functional theory; heme; metabolism.

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Figures

Figure 1
Figure 1
SMARTCyp algorithm and the generation of the atom reactivity library in the form of activation energies. The SMARTS rules in the figure are simplified.
Figure 2
Figure 2
Energy ranges in the SMARTS rules for the various atom types. Example structures for the drug fragments giving the smallest and largest activation energies for each atom type are shown below and above the energy bars.
Figure 3
Figure 3
Experimental SOMs and SMARTCyp predictions for five compounds. The gray circles represent experimentally found SOMs. Arrows and numbers represent the top three predicted sites by SMARTCyp.
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National Institutes of Health, United States