Predict the Site of Metabolism

Other docking algorithms such as Glide [33], Dock [34] and GOLD [35] have also been used to predict the site of metabolism, and a recent study compared the performance of multiple algorithms in the field of cytochrome P450s [36],... 

The Effect of the Structure in the Different Methods to Predict the Site of Metabolism... 

A methodology is described to predict the site of metabolism and the potential MBI by CYPs for compounds as well as subsequent possible phase II metabolism by UGTs. On average, for about 85% of the cases, the method predicted the right site of metabolism within the first two atoms in the ranking list and for more than 80% of the MBI inhibitors. The same methodology can also be applied to predict phase II, UGT-mediated metabolism. 

The methodology is very fast and completely automated. To predict the site of metabolism for drug-like substrates, the method requires few seconds per molecule. It is important to point out that the method uses neither any training set nor any statistical model or supervised technique, and it has proven to be predictive for extensively diverse validation sets preformed in different pharmaceutical companies. 

Cruciani, G., Aristei, Y., Vianello, R. and Baroni, M. (2005) GRID-derived molecular interaction fields for predicting the site of metabolism in human cytochromes, in Molecular Interaction Fields (ed. G. Cruciani) Wiley-VCH Verlag GmbH, Weinheim, pp. 273-290. 

ArQule provides professional services and products including metabolism models for CYP 3A4, 2D6, and 2C9. The metabolism models are based on combined empirical/quantum chemical approaches and are aimed at predicting the site of metabolism, enzyme-substrate binding affinities (2D6 and 2C9), and relative rates of metabolism at discrete sites within a molecule (274). 

Finally MIFs will be used to explain cytochrome P450 (CYP) 3A4 inhibition. The use of METASITE in understanding and predicting the site of metabolism... 

CRID-Derived Molecular Interaction Fields for Predicting the Site of Metabolism in Human Cytochromes... 

Table 12.1 shows that in more than 70% of CYP2C9 reactions, the first option selected by the methodology matches the experimental one. Moreover, in more than 16% of cases, the second atom is that which fits the experimental one. Therefore, in considering the overall ranking list for the single and multiple sites of metabolism, the methodology predicts the site of metabolism for CYP2C9 within the first two atoms selected in approximately 86% of the reactions, independent of the conformer used. 

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