White Anita C, Mueller Richard A, Gallavan Robert H, Aaron Sid, Wilson Alan G E
Department of Preclinical Development, Pharmacia Corporation, St Louis, MO 63167, USA.
Mutat Res. 2003 Aug 5;539(1-2):77-89. doi: 10.1016/s1383-5718(03)00135-9.
We have conducted an evaluation of three of the most widely used commercial toxicity prediction programs, Toxicity Prediction by Komputer Assisted Technology (TOPKAT), Deductive Estimation of Risk from Existing Knowledge (DEREK) for Windows (DfW) and CASETOX. The three programs were evaluated for their ability to predict Ames test mutagenicity using 520 proprietary drug candidate (Test set 1) and 94 commercial (Test set 2) compounds. The study demonstrates that these three commercially available programs are useful, with limitations in their ability to predict mutagenicity over a wide range of chemical space, i.e. global predictivity. Individually, each of the programs performed at an acceptable level for overall accuracy, i.e. the ability to predict the correct outcome. However, analysis of the predictions indicates that the overall accuracy figure is heavily weighted by the ability of the programs to correctly predict non-mutagens, whereas none of the programs individually performed well in the prediction of novel mutagenic structures, i.e. Ames positive compounds. The performance of these programs' in predicting Ames positive mutagens appeared to be independent of the chemical utility of the compound, i.e. industrial, agricultural or pharmaceutical. The combination of program predictions provided some improvement in overall accuracy, sensitivity and specificity.
我们对三种使用最为广泛的商业毒性预测程序进行了评估，即计算机辅助技术毒性预测程序（TOPKAT）、基于现有知识的风险演绎评估程序（DEREK）Windows版（DfW）以及CASETOX。使用520种专利候选药物（测试集1）和94种商业化合物（测试集2）对这三种程序预测艾姆斯试验致突变性的能力进行了评估。该研究表明，这三种商用程序是有用的，但在预测广泛化学空间内的致突变性（即全局预测性）方面存在局限性。就总体准确性而言，即预测正确结果的能力，这三种程序各自的表现都处于可接受水平。然而，对预测结果的分析表明，总体准确性数据在很大程度上受程序正确预测非致突变物能力的影响，而在预测新型致突变结构（即艾姆斯试验阳性化合物）方面，没有任何一个程序表现出色。这些程序在预测艾姆斯试验阳性致突变物方面的表现似乎与化合物的化学用途无关，如工业、农业或制药用途。程序预测结果的组合在总体准确性、敏感性和特异性方面有一定程度的提高。
