In silico toxicology for the pharmaceutical sciences☆

Genotoxic Impurities in Pharmaceuticals

“…In silico toxicology is the application of computer technologies to analyze existing data, model, and predict the toxicological activity of a substance. In sequence, toxicologically based QSARs are mathematical equations used as a predictive technique to estimate the toxicity of new chemicals based upon a model of a training set of chemicals with known activity and a defined chemical space (Valerio, 2009). Ashby and Tennant (1991) reported some correlations of electrophilicity with DNA reactivity (assessed by Ames-testing data) for about 300 chemicals and elucidated the concept of structural alerts for genotoxic activity in the 1980s/1990s.…”

“…As error (e.g. incorrect molecular structure or erroneous data from toxicology studies of a chemical) is introduced into the model, amplification of that error is generated and represented in the prediction (Benigni et al, 2005;Valerio, 2009). Cunningham et al (1998) investigated a SAR analysis of the mouse subset of the carcinogenic potency database (CPDB) which also included chemicals tested by the US national toxicology program (NTP).…”

“…The other limitation to currently available QSARs is the lack of models for organometallics, complex mixtures (e.g. herbal extracts), and high molecular weight compounds such as polymers (Valerio, 2009). However, the QSAR predictive software offers a rapid, reliable, and cost effective method of identifying the potential risk of chemicals that are well represented in QSAR training data sets, even when experimental data are limited or lacking (Kruhlak et al, 2007).…”

Computational science in drug metabolism and toxicology

“…QSAR predictive modeling has been researched and tested at the FDA/Center for Drug Evaluation and Research for several years. Recent reviews, commentary and research reports on computational toxicology approaches focused on QSAR evaluations and use at the FDA can be found [1][2][3]. In the EU, clearly there are well-recognized reasons for using computational approaches.…”

“…These expert assessments are refreshing and necessary to ensure predictive QSARs that are available commercially are taken with caution before acceptance of their use. Recent reviews on the limitations of QSARs and modeling are available noting it is rare and unrealistic that a QSAR prediction alone would support on a stand-alone basis the safety of a chemical in the US [1,2,6]. The article by the FDA/CFSAN in this issue also touches on this subject [7].…”