Rules relating hepatotoxicity with structural attributes of drugs

The relationship between molecular structures of drugs and their hepatotoxicity was studied by characterizing their structure in a new way and using formal concept analysis, a mathematical technique to condense knowledge into particular rules, which does not imply linearly assumptions as many conventional statistical techniques. The structural characterization was based on molecular descriptors and molecular frameworks, further decomposed into structural elements, rings, and bridges. The methodology was applied to drugs in the liver toxicity knowledge base database with the potential to cause drug-induced liver injury. Numbers of atoms and bonds along with the aromatic ratio were suitable descriptors for such drugs. The higher the number of rings and asymmetric structural elements in their terminal ring systems, the higher is the probability of hepatotoxicity. Rules were found which may help to design drugs which are unlikely to be hepatotoxic.

本研究通过一种全新的结构表征方式，并借助形式概念分析（Formal Concept Analysis）——一种可将知识凝练为特定规则的数学方法，其未如诸多传统统计方法那般引入线性假设——探究了药物分子结构与肝毒性之间的关联。该结构表征基于分子描述符（molecular descriptors）与分子骨架（molecular frameworks），并进一步拆解为结构单元、环系与桥键。本方法被应用于肝毒性知识库中具备引发药物诱导肝损伤（drug-induced liver injury）潜力的药物样本。研究发现，原子数、键数以及芳香性占比可作为此类药物的适宜描述符；药物末端环系中的环数与非对称结构单元越多，其引发肝毒性的概率就越高。本研究得到的相关规则可为设计低肝毒性风险的药物提供参考。