Nunes Renata Rachide, Costa Marina Dos Santos, Santos Bianca Dos Reis, Fonseca Amanda Luisa da, Ferreira Lorena Sales, Chagas Rafael Cesar Russo, Silva Alisson Marques da, Varotti Fernando de Pilla, Taranto Alex Gutterres
Universidade Federal de São João Del-Rei, Laboratório de Química Farmacêutica Medicinal, Divinópolis, MG, Brasil.
Universidade Federal de São João Del-Rei, Núcleo de Pesquisa em Química Biológica, Divinópolis, MG, Brasil.
Mem Inst Oswaldo Cruz. 2016 Dec;111(12):721-730. doi: 10.1590/0074-02760160207. Epub 2016 Nov 10.
The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays.
疟疾控制中的主要挑战一直是耐药性寄生虫的出现。耐药疟原虫的存在增加了对新型抗疟药物的需求。分子建模技术已被用作开发新药的工具。在本研究中，我们针对四种疟疾靶点：疟原虫天冬氨酸蛋白酶-IV、疟原虫天冬氨酸蛋白酶-II、恶性疟原虫组织蛋白酶-II和PfATP6，对一种吡唑衍生物（Tx001）进行了虚拟筛选。为每个分子靶点建立了受试者工作特征曲线和曲线下面积（AUC）。疟原虫天冬氨酸蛋白酶-IV、疟原虫天冬氨酸蛋白酶-II和恶性疟原虫组织蛋白酶-II获得的AUC值分别为0.64、0.92和0.94。所有对接模拟均使用AutoDock Vina软件进行。配体Tx001与PfATP6的相互作用比与参考化合物的相互作用更好（-12.2对-6.8千卡/摩尔）。Tx001-PfATP6复合物在NAMD程序上进行的真空中分子动力学模拟。配体Tx001与毒胡萝卜素对接在相同的结合位点，毒胡萝卜素是PfATP6的天然抑制剂。化合物TX001在体外对恶性疟原虫菌株（W2）和人细胞系（WI-26VA4）进行了评估。发现Tx001对恶性疟原虫有活性（IC50 = 8.2 μM），对WI-26VA4无活性（IC50 > 200 μM）。进一步的配体优化循环为对接和生物学测定带来了新的前景。
