Predicting Metabolism — Meteor

Another program available form Lhasa Ltd. is Meteor, software that allows predicting metabolic pathways of xenobiotic compounds [13-15], Again, the program uses expert knowledge in form of rules to predict the metabolic pathway of compounds. The predictions are presented in metabolic trees, similar to a synthesis tree, and may be filtered according to the likelihood of metabolites. 

Starting with a structure entered with MDL ISlS/Draw or imported as MDL Molfile or ISIS Sketch files (.skc), the user can define constraints to restrict the reported metabolites. Unconstrained generation of metabolic pathways from a compound would lead to combinatorial explosion of the amount of metabolites. Constraints can be defined for the following  

The software also allows comparisons between potentially competing biotransformations and provides comments and literature references as evidence to support its predictions. The resulting metabolic transformation tree view allows evaluating the metabolic path for potentially harmful metabolites. 

Meteor can be interfaced with the MetaboLynx mass spectrometer software from Waters Corporation to integrate mass spectrometry data from metabolism studies directly. MetaboLynx is part of the Waters MassLynx Application Managers, a suite of mass spectrometry instrument software [16]. It is designed for automated metabolism studies with data from LC/MS or LC/MS/MS time-of-flight (TOP) experiments. MetaboLynx is able to detect peaks in an LC/MS data file resulting from in vitro or in vivo biotransformation and provides a list of elemental formulae for unidentified components in a mass spectrum. Meteor uses these data to filter the list of predicted metabolites. System requirements are similar to DEREK for Windows. 

Other rule-based systems include MetabolExpert from CompuDrug Inc., designed for initial estimation of the structural formula of metabolites, and MetaDrug from GeneGo. MetaDrug splits query compounds into metabolites, runs them through QSAR models, and visualizes them in pathways, cell processes, and disease networks. An extensive overview on the commercially available systems was given by Ekins [17]. 

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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]. 

DfW predictions include information about the mechanism of activity, for example metabolic steps necessary for toxicity. For a more detailed analysis of the toxicity of a compound and its metabolites DfW can be used in combination with an in silico program for the prediction of metabolites. LHASA Limited offers such a program with the name METEOR. For the combination of these two systems, first the metabolites of a compound are predicted by METEOR. These metabolites are then sent to DfW for the prediction of toxicity of the compound and its predicted metabolites. 

Meteor is knowledge-based software that allows predicting metabolic pathways of xenobiotic componnds. 

METEOR Rule-based Metabolite prediction software Predicts the metabolic fate of chemicals Displays results as a metabolic tree. User can filter results for likely metabolites. Links directly to MetaboLynx for analysis of mass spectrometry data www.lhasalimited.org... 

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

Greene N, Judson PN, Langowski JJ, Marchant CA. Knowledge-based expert systems for toxicity and metabolism prediction DEREK, StAR and METEOR. SAR QSAR Environ Res 1999 10 299-314. 

Testa B, Balmat AL, Long A, Judson P. Predicting drug metabolism—an evaluation of the expert system METEOR. Chem Biodiversity 2005 2 872-85. 

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. 

Knowledge-based methods are those based on the application of certain rules to describe the metabolism. These rules could be defined as chemical reactions relating structure and biotransformations to predict the metabolic fate of a query chemical structure, as in the Meteor approach [26], or alternatively they could be obtained by fragment analysis of a metabolic database as performed in the SPORCalc (Substrate Product Occurrence Ratio Calculator) system [27]. 

Testa, B., Balmat, A.L., Long, A. and Judson, P. (2005) Predicting drug metabolism-an evaluation of the expert system METEOR. Chemical and Biodiversity, 2, 872-885. 

METEOR Expert system for the prediction of metabolic transformations... 

Several expert systems have been developed for the prediction of chemical fate within organisms, or primarily metabolism. Three of the best known are META (Klopman et al., 1994 Talafous et al., 1994), MetabolExpert (Darvas et al 1999) initiated as a research project by CompuDrug in 1985, and a more recent program METEOR (LHASA Ltd., University of Leeds, U.K.). A formal comparison of the predictions of these systems does not appear to have been performed and published, although the predictions of META, MetabolExpert, and several human experts for a drug were presented for comparative purposes (Wilbury, 1999). 

The METEOR expert system, first marketed in 1999, is a newer development than MetabolExpert or META. It provides qualitative predictions of metabolic fate in mammals and the likelihood of individual biotransformations. The system, developed and marketed by LHASA Ltd., evolved out... 

Greene N, Judson PN, Langowski JJ, Marchant CA (1999) Knowledge-based expert systems for toxicity and metabolism prediction DEREK, StAR and METEOR. SAR QSAR Environ Res 10 299-314 Greene N (2002) Computer systems for the prediction of toxicity an update. Adv Drug Deliv Rev 54 417—431 Lhasa homepage http //www.chem.leeds.ac.uk/luk/... 

Ali MA, Long A. Recent advances in Meteor Metabolism prediction for heteroaromatic ring systems. Drug Metab Rev 2005 37(1) 159. 

A number of in silico models exist for the prediction of metabolism, e.g., Meteor [34, 35] or the OECD Toolbox [36], However, these systems normally only give a qualitative indication of the metabolites formed rather than a quantification [37],... 

Greene, N., et al. Knowledge-Based Expert System for Toxicity and Metabolism Prediction DEREK, StAR, and METEOR, SAR QSAR, Environ. Res., 10, 299, 1997. 

Testa, B. et al., Predicting drug metabolism—An evaluation of the expert system METEOR, Chem. Biodivers., 2(7), 872, 2005. 

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