OBJECTIVE: The aim of this study was to identify potential α-TcCA inhibitors with trypanocide activity.
METHODS: A maximum common substructure (MCS) and molecular docking were used to carry out a ligand- and structure-based virtual screening of ZINC20 and MolPort databases. The compounds selected were evaluated in an in vitro model against the NINOA strain of Trypanosoma cruzi, and cytotoxicity was determined in a murine model of macrophage cells J774.2.
RESULTS: Five sulfonamide derivatives (C7, C9, C14, C19, and C21) had the highest docking scores (-6.94 to -8.31 kcal/mol). They showed key residue interactions on the active site of the α-TcCA and good biopharmaceutical and pharmacokinetic properties. C7, C9, and C21 had half-maximal inhibitory concentration (IC50) values of 26, 61.6, and 49 μM, respectively, against NINOA strain epimastigotes of Trypanosoma cruzi.
CONCLUSIONS: Compounds C7, C9, and C21 showed trypanocide activity; therefore, these results encourage the development of new trypanocidal agents based on their scaffold.
目的:本研究的目的是鉴定具有锥虫杀灭剂活性的潜在α-TcCA抑制剂。
方法:使用最大共同亚结构(MCS)和分子对接对ZINC20和MolPort数据库进行基于配体和结构的虚拟筛选。在针对克氏锥虫NINOA菌株的体外模型中评估所选化合物,并在巨噬细胞J774.2的小鼠模型中确定细胞毒性。
结果:五种磺酰胺衍生物(C7,C9,C14,C19和C21)的对接得分最高(-6.94至-8.31kcal/mol)。它们显示了α-TcCA活性位点上的关键残基相互作用以及良好的生物制药和药代动力学特性。C7、C9和C21的半数最大抑制浓度(IC50)值为26、61.6和49μM,分别,针对克氏锥虫的NINOA毒株。
结论:化合物C7、C9和C21显示出锥虫杀菌活性;因此,这些结果鼓励了基于支架的新型杀锥虫剂的开发。