Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, Cidade Universitária - Castelo Branco III, João Pessoa, PB, Brazil.
ChemMedChem. 2018 Mar 20;13(6):634-645. doi: 10.1002/cmdc.201700743. Epub 2018 Feb 6.
Chagas disease is an endemic disease caused by Trypanosoma cruzi, which affects more than eight million people, mostly in the Americas. A search for new treatments is necessary to control and eliminate this disease. Sesquiterpene lactones (SLs) are an interesting group of secondary metabolites characteristic of the Asteraceae family that have presented a wide range of biological activities. From the ChEMBL database, we selected a diverse set of 4452, 1635, and 1322 structures with tested activity against the three T. cruzi parasitic forms: amastigote, trypomastigote, and epimastigote, respectively, to create random forest (RF) models with an accuracy of greater than 74 % for cross-validation and test sets. Afterward, a ligand-based virtual screen of the entire SLs of the Asteraceae database stored in SistematX (1306 structures) was performed. In addition, a structure-based virtual screen was also performed for the same set of SLs using molecular docking. Finally, using an approach combining ligand-based and structure-based virtual screening along with the equations proposed in this study to normalize the probability scores, we verified potentially active compounds and established a possible mechanism of action.
恰加斯病是一种由克氏锥虫引起的地方性疾病，影响着超过 800 万人，主要集中在美洲。为了控制和消除这种疾病，有必要寻找新的治疗方法。倍半萜内酯（SLs）是一类有趣的次生代谢物，是菊科植物的特征，具有广泛的生物活性。我们从 ChEMBL 数据库中选择了一组具有多样性的 4452、1635 和 1322 个结构，这些结构分别针对三种克氏锥虫寄生虫形式（无鞭毛体、鞭毛体和滋养体）进行了活性测试，以创建随机森林（RF）模型，交叉验证和测试集的准确率均高于 74%。之后，我们对存储在 SistematX 中的菊科植物数据库中的所有 SLs 进行了基于配体的虚拟筛选（1306 个结构）。此外，我们还使用分子对接对同一组 SLs 进行了基于结构的虚拟筛选。最后，我们采用结合配体和基于结构的虚拟筛选以及本研究中提出的方程来归一化概率评分的方法，验证了潜在的活性化合物，并建立了可能的作用机制。
