Metabolism prediction program

The virtual compounds can be input into metabolism prediction programs, such as Metabolexpert [30] or Meteor [31], to identify principal pathways of expected drug metabolism. 

For the prediction of metabolism, commercial programs have been developed that allow the likely sites of enzymatic attack to be identified for a molecule, indicating potential routes of metabolism and likely metabolites. The use of such programs in the prediction of metabolism has been reviewed by Langowski and Long (2002), and this topic is discussed in more detail elsewhere in this book (see Chapter 10). 

Metabolism prediction through in silica methods may be possible in the future, although there is still a great deal of technical development needed before it is a viable alternative (van de Waterbeemd and Gifford, 2003). Predictive metabolism programs may allow metabolism scientists and medicinal chemists to obtain metabolic rate or site of metabolism information prior to first synthesis of compounds. The majority of the methods in this area that have... 

Although DEREK cannot of itself handle metabolism, a sister program, METEOR [97], allows the prediction of metabolites, which can then be assessed by DEREK. 

Darvas F. Predicting metabolic pathways by logic programming. J Mol Graph 1988 6 80-86. 

Cruciani et al. [92] have developed the program Metasite for the prediction of the site of oxidative metabolism by CYP450 enzymes. Metasite uses GRID molecular interaction fields to fingerprint both structures of CYP450s (from homology models or crystal structures) and test substrates and then matches the fields. Zhou et al. [93] showed that Metasite was able to correctly predict the site(s) of metabolism 78% of the time for 227 CYP3A4 substrates. Caron et al. [94] used Metasite to predict the oxidative metabolism of seven statins. 

C. De Maria, D. Grassini, F. Vozzi, B. Vinci, A. Landi, A. Ahluwalia, and G. Vozzi, Hemet Mathematical model of biochemical pathways for simulation and prediction of hepatocyte metabolism. Comput. Methods Programs Biomed. (2008). 

A number of approaches are available or under development to predict metabolism, including expert systems such as MetabolExpert (Compudrug), Meteor (Lhasa), MetaFore [42] and the databases Metabolite (MDL) and Metabolism (Synopsys) [43]. Ultimately such programs may be linked to computer-aided toxicity prediction based on quantitative structure-toxicity relationships and expert systems for toxicity evaluation such as DEREK (Lhasa) (see also Chapter 8) [44]. 

Preliminary predictions of absorption of a substance can be made from its physico-chemical properties if no other information is available. Also elaborate computer programs are available that make predictions about, e.g., dermal penetration or metabolic pathways. However, these systems have often not been extensively validated against appropriate experimental data and it is not always certain if the results obtained in such models reflect the situation in vivo. On this basis, modeled data should only be used for risk assessment purposes where it is supported by other kinds of evidence. 

The META system (291-293) is an expert system, based on well-established sources, for predicting the sites of potential enzymatic attack and the metabolites formed by metabolic transformations. The program uses dictionaries of biotransformation operators, which are created by experts to represent known metabolic paths. Currently, META can be combined with one of the following dictionaries mammalian metabolism, aerobic biodegradation, anaerobic biodegradation, and metabolic transformation reactions (291). 

Klopman, G. and Tu, M. (1999) META. A program for the prediction of the products of mammal metabolism of xenobiotics. Blackwell Science, Oxford, UK. 

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