Grupo de Estudos em Quimica Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Quimica de Sao Carlos, Universidade de Sao Paulo, 13560-970 Sao Carlos, SP, Brazil.
J Chem Inf Model. 2010 Jan;50(1):97-109. doi: 10.1021/ci900074t.
Cytochrome P450 (CYP450) is a class of enzymes where the substrate identification is particularly important to know. It would help medicinal chemists to design drugs with lower side effects due to drug-drug interactions and to extensive genetic polymorphism. Herein, we discuss the application of the 2D and 3D-similarity searches in identifying reference structures with higher capacity to retrieve substrates of three important CYP enzymes (CYP2C9, CYP2D6, and CYP3A4). On the basis of the complementarities of multiple reference structures selected by different similarity search methods, we proposed the fusion of their individual Tanimoto scores into a consensus Tanimoto score (T(consensus)). Using this new score, true positive rates of 63% (CYP2C9) and 81% (CYP2D6) were achieved with false positive rates of 4% for the CYP2C9-CYP2D6 data set. Extended similarity searches were carried out on a validation data set, and the results showed that by using the T(consensus) score, not only the area of a ROC graph increased, but also more substrates were recovered at the beginning of a ranked list.
细胞色素 P450（CYP450）是一类酶，其中底物的鉴定尤为重要。这将有助于药物化学家设计具有更低副作用的药物，因为药物-药物相互作用和广泛的遗传多态性。本文讨论了二维和三维相似性搜索在识别具有更高能力的参考结构中的应用，这些参考结构可以检索三种重要 CYP 酶（CYP2C9、CYP2D6 和 CYP3A4）的底物。基于不同相似性搜索方法选择的多个参考结构的互补性，我们提出将它们各自的 Tanimoto 分数融合为共识 Tanimoto 分数（T（共识））。使用这个新的分数，对于 CYP2C9-CYP2D6 数据集，CYP2C9 的真阳性率为 63%，CYP2D6 的真阳性率为 81%，假阳性率为 4%。对验证数据集进行了扩展相似性搜索，结果表明，使用 T（共识）分数不仅增加了 ROC 图的面积，而且在排名列表的开头还恢复了更多的底物。
