Predicting Metabolism

All drugs are subject to metabolic process, in general these process serve to increase the polarity of molecules in an effort to increase excretion. Whilst the impact of metabolism on the drug duration of action is major concern, a knowledge of the metabolic routes can be useful in other ways. In particular, knowledge of the mechanism may highlight potential high energy intermediates that could contribute to toxicity, the identification of metabolites that in themselves may or may not have pharmacological effects, changes in physicochemical properties resulting from biotransformation.

Several approaches have been used to produce in silico systems to predict metabolism,

Local solutions, intended to predict the activity of a single enzyme (and often only within a chemical series). These models can be based on pharmacophores (QSAR) derived from known substrates, or docking potential substrates into the active site of the enzyme, and/or quantum mechanical calculations used to predict reactivity.
The majority of drug are metabolised by Cytochome P450 enzymes that exist predominantly in the liver. Whilst similar in structure the CYPs have distinct substrate specificities and models for each of the enzymes need to be derived. The recent crystallization of CYP P450s should help refine these models. A number of the computational models for predicting CYP mediated metabolism have been reviewed (European Journal of Medicinal Chemistry Volume 41, Issue 7, July 2006, Pages 795-808).

SMARTCyp is a method for prediction of which sites in a molecule that are labile for metabolism by Cytochromes P450 isoform 3A4. It is also a reactivity model which is applicable to all P450 isoforms. The method has been published as SMARTCyp – a 2D-method for Prediction of Cytochrome P450 Mediated Drug Metabolism in ACS Medicinal Chemistry Letters, DOI: 10.1021/ml100016x

Global solutions, intended to predict the metabolism of any molecule exposed to a complex biological system. This type of solution is often rule-based and uses an extensive database of known biotransformations
Programs such as MetaDrug (Expert Opin. Drug Metab. Toxicol. (2005) 1(1)) uses a series of rules together with a series of QSAR models to predict metabolic transformations, and includes both phase I and phase II metabolism. The transformations described include among many:- C,N,S and P-oxidation, including dealkylation, hydroxylation, double bond peroxidation, Quinone formation, reduction (nitro, carbonyl, azo, sulphur), hydrolysis (esters, amides, phosphates, epoxides), glucoronidation, sulphation, glutathione conjugation, methyl transferases, amino acid conjugation. Other programs using similar approaches include Meteor, (Pure Appl.Chem., Vol.76, No.5, pp.907–914, 2004) and Meta.
In general I’ve found these products very useful for identifying all potential metabolic sites, however they can over-predict and you may well find many of the potential metabolic routes have negligible contributions in vivo.

See Also Metabolism
See Also CYP450 Interactions

Last Updated 23 April 2010
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