Guido Rafael V C, Trossini Gustavo H G, Castilho Marcelo S, Oliva Glaucius, Ferreira Elizabeth I, Andricopulo Adriano D
Laboratório de Química Medicinal e Computacional, Centro de Biotecnologia Molecular Estrutural, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos-SP, Brazil.
J Enzyme Inhib Med Chem. 2008 Dec;23(6):964-73. doi: 10.1080/14756360701810322.
Chagas' disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. Cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for antitrypanosomal chemotherapy. In the present work, classical two-dimensional quantitative structure-activity relationships (2D QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 45 thiosemicarbazone and semicarbazone derivatives as inhibitors of T. cruzi cruzain. Significant statistical models (HQSAR, q(2) = 0.75 and r(2) = 0.96; classical QSAR, q(2) = 0.72 and r(2) = 0.83) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 10 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r(2)(pred) = 0.95; classical QSAR, r(2)(pred) = 0.91), indicating the existence of complementary between the two ligand-based drug design techniques.
恰加斯病是一种寄生虫感染病，广泛分布于拉丁美洲，对人类的发病率和死亡率造成了毁灭性影响。克氏锥虫半胱氨酸蛋白酶（Cruzain）是克氏锥虫的主要半胱氨酸蛋白酶，是抗锥虫化疗的一个有吸引力的靶点。在本研究中，对45种硫代氨基脲和氨基脲衍生物作为克氏锥虫Cruzain抑制剂的训练集进行了经典二维定量构效关系（2D QSAR）和全息定量构效关系（HQSAR）研究。获得了显著的统计模型（HQSAR，交叉验证系数q(2)=0.75，决定系数r(2)=0.96；经典QSAR，q(2)=0.72，r(2)=0.83），表明它们对未测试化合物具有一致性。然后使用这些模型评估一个包含10种未包含在训练集中的化合物的外部测试集，预测值与实验结果高度吻合（HQSAR，预测决定系数r(2)(pred)=0.95；经典QSAR，r(2)(pred)=0.91），表明这两种基于配体的药物设计技术之间存在互补性。
