Toxicity expert systems Derek

Another approach to predict toxicity is basing on structure-activity-relationship (SAR), which means the qualitative relationship between a specific chemical structure and their biological/toxicological activity, e.g. the expert system DEREK is based on SAR prediction. In SAR the occurrence of specific substructures in a molecule are correlated to be responsible and necessary for a biological/toxicological activity. 

A number of commercial expert systems have been applied to screen drug libraries. For instance, DEREK, TOPKAT, MultiCASE, and many other systems all have possibilities in this regard. However, it should be noted that for broad screening only compounds with toxicity associated with them can be identified, and hence these are very crude measures of hazard assessment. The use of expert systems to screen libraries is fraught with dangers, not least that no performance statistics are available for these systems being used for such an application. It is also highly probable that the vast majority of predic-... 

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. 

DEREK Expert system for the prediction of toxicity (genotoxicity, carcinogenicity, skin sensitization, etc.)... 

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]. 

An example of another approach is DEREK, a pnblicly available expert system designed to assist chemists and toxicologists in predicting toxicological hazards based on analysis of chemical strnctnre (see table 9.1). DEREK differs from other compnter methods for toxicity prediction in that it makes qnalitative rather than qnantitative predictions and does not rely on algebraic or statistical relationships. 

The Use of Expert Systems for Toxicity Prediction Illustrated with Reference to the DEREK Program... 

The two major independent in silico methods for the prediction of toxicity are quantitative-structure-activity-relationship (QSAR) and expert systems (e.g. DEREK, MultiCASE). QSAR means the quantitative relationship between a chemical structure and its biological/ toxicological activity with the help of chemical descriptors that are generated from the... 

Expert systems have been defined as any formal systems , which make predictions about the toxicity of chemicals. All expert systems for the prediction of toxicity are built on experimental data and/or rules derived from such data (Dearden 2003). The expert systems can be further divided into two subclasses based on the method of generating rules. The one method is a knowledge- or rule-based expert system, for which experts/toxicologists create rules based on a list of structural features that have been related to a specified toxicity (Durham and Pearl 2001). An example of a typical knowledge- or rule-based system is DEREK, which will be described later. 

There are a number of commercial expert in silico systems available for the prediction of toxicity. Examples of knowledge-based expert systems are DEREK (Lhasa, Leeds, UK), Hazard Expert (ComGenex, San Francisco, CA, USA), Oncologic (San Francisco, CA, USA) and COMPACT (University of Surrey, Guilford, UK). Examples of statistically-based systems are MultiCASE (MultiCase, Beachwood, OH, USA),... 

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/... 

A number of computer-based expert systems have emerged that are more directly focused on toxicity evaluation these are HAZARDEXPERT (with its accompanying package, METABOLEXPERT), DEREK,86 and COMPACT.87-91... 

In silico tools make a significant contribution to the SAR-based early identification of potential toxicity. An increasing volume of published preclinical and clinical toxicity data are collected and used to build structure-related searchable databases. These expert knowledge databases can analyze chemical structures and match them with potential mechanisms of toxicity. DEREK for Windows (Lhasa Ltd.)39 is one of such broadly used knowledge-based expert systems to provide toxicology alerts for new compounds. Although certainly not comprehensive, numerous efforts have been made to predict hepatotoxicity. Recently,... 

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

Computational approaches to predicting toxicity are based on expert systems containing empirical or computationally derived rules, typically encoded via stmctural fragments that could potentially cause toxicity. Several databases are available commercially rule-based DEREK and HazardExpert, as well as systems based on automated QSAR—TOPKAT and CASETOX. Computational methods for predicting drug toxicity are reviewed in reference 57. 

Combes, R.D. and Rodford, R.A. (2004). The use of expert systems for toxicity prediction illustrated with reference to the DEREK program, in M.T.D. Cronin and D.J. Livingstone (eds.). Predicting Chemical Toxicity and Fate, Boca Raton, EL CRC Press, pp. 193-204. 

---