Toxmatch-A chemical classification and activity prediction tool based on similarity measures
ABSTRACT Chemical similarity forms the underlying basis for the development of (Quantitative) Structure-Activity Relationships ((Q)SARs), expert systems and chemical groupings. Recently a new software tool to facilitate chemical similarity calculations named Toxmatch was developed. Toxmatch encodes a number of similarity indices to help in the systematic development of chemical groupings, including endpoint specific groupings and read-across, and the comparison of model training and test sets. Two rule-based classification schemes were additionally implemented, namely: the Verhaar scheme for assigning mode of action for aquatic toxicants and the BfR rulebase for skin irritation and corrosion. In this study, a variety of different descriptor-based similarity indices were used to evaluate and compare the BfR training set with respect to its test set. The descriptors utilised in this comparison were the same as those used to derive the original BfR rules i.e. the descriptors selected were relevant for skin irritation/corrosion. The Euclidean distance index was found to be the most predictive of the indices in assessing the performance of the rules.
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ABSTRACT: This article provides an overview of the use of computational methods in chemicals hazard and risk assessment under the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation. The key aspects of the REACH guidance on the assessment of chemicals are discussed that treat the possible stepwise (tiered) approach combining multiple computational methods in assessing chemicals. Several publicly accessible software tools for the computer-based estimation of chemical hazard, developed by the European Commission's Joint Research Centre (JRC), are described.
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ABSTRACT: Although inappropriate pharmacokinetic properties were a major cause of attrition in the 1990s, safety issues are recognized as today's single largest cause of drug candidate failure. It is expected that the right balance of in vivo, in vitro and computational toxicology predictions applied as early as possible in the discovery process will help to reduce the number of safety issues. This review focuses on recent developments in computational toxicology. Direct modeling of toxic endpoints has been deceiving and hampered the wide acceptance of computer predictions. The current trend is to make simpler predictions, closer to the mechanism of action, and to follow them up with in vitro or in vivo assays as appropriate.Drug discovery today 10/2009; 15(1-2):16-22. DOI:10.1016/j.drudis.2009.09.010 · 6.69 Impact Factor
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ABSTRACT: It has been estimated that reproductive and developmental toxicity tests will account for a significant proportion of the testing costs associated with REACH compliance. Consequently, the use of alternative methods to predict developmental toxicity is an attractive prospect. The present study evaluates a number of computational models and tools which can be used to aid assessment of developmental toxicity potential. The performance and limitations of traditional (quantitative) structure-activity relationship ((Q)SARs) modelling, structural alert-based expert system prediction and chemical profiling approaches are discussed. In addition, the use of category formation and read-across is also addressed. This study demonstrates the limited success of current modelling methods when used in isolation. However, the study also indicates that when used in combination, in a weight-of-evidence approach, better use may be made of the limited toxicity data available and predictivity improved. Recommendations are provided as to how this area could be further developed in the future.Reproductive Toxicology 12/2009; 30(1):147-60. DOI:10.1016/j.reprotox.2009.12.003 · 3.23 Impact Factor