34种待选药物诱变性预测及分子结构基础分析

Prediction of mutagenicity and analysis of structure basis of 34 drug candidates

CASE (computer automated structure evaluation)系统是一种根据化学物质结构预测其诱变性或致癌性的计算机辅助系统,本文介绍了一种可在IBM 286微机上运行的CASE系统,通过对数千种已知生物活性的化学物质结构的综合分析,建立了与活性有关的局部结构(片段)数据库和知识库,并对34种待选药物Ames试验作了预测,与文献报道基本一致(96.4％);同时也对其分子基础作了分析,由于CASE的预测程序是由计算机完成的,速度极快,因此是设计和筛选低毒药物有效的辅助方法,并可为进一步选择生物学检测方法提供参考。

The CASE (computer-automated structure evaluation) methodology in VAX II was developed by Rosenkranz et al. Recently, we established an expert system of CASE in microcomputers to identify structure moieties responsible for mutagenicity (Ames test). CASE selects its own descriptors from a learning set composed of active and inactive molecules. The descriptors consist of either activated or inactivated fragments. When the structure of an unknown drug candidate enters the computer, all the possible fragments ranging from 2 to 10 atoms accompanied by their hydrogens will be generated and these compared with the previously identified descriptors. On the basis of the presence and / or absence of these descriptors, CASE predicts mutagenicity of the drug candidates of unknown activity.Genetic toxicology tests have become an important factor in the safety assessment of the new drugs and chemicals. All the drug candidates which induce positive responses in genetic toxicology tests can not be applied, although these have shown much more effective. The expert system of CASE may provide the re-sults of the tests of the drug candidates before they were synthesized , so that CASE is a predictive screening method.The purpose of this paper is to report the results of CASE prediction of 34 drugs or potential drugs in the Salmonella / microsome (Ames) test. The activities of mutagenicity of these drug candidates in short-term screening tests have been reported by Aaron, C.S.. The CASE identified 16 fragments which accounted for the mutagenicity, or showed a lack, thereof, of most of the drug candidates. The mutagenicity of the two of 34 drug candidates has not been reported by Aaron; CASE predicted the positive response. The prediction of the other 32 drugs or potential drugs showed the same result as reported by Aaron. The specificity was unexpectedly high (96.4%). This result suggests the effectivity of the CASE expert system for the prediction of mutagenicity.