Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.
J Comput Aided Mol Des. 2013 Oct;27(10):859-71. doi: 10.1007/s10822-013-9685-z. Epub 2013 Oct 25.
Increased resistance of Plasmodium falciparum to most available drugs challenges the control of malaria. Studies with protease inhibitors have suggested important roles for the falcipain family of cysteine proteases. These enzymes act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. In order to find potential new antimalarial drugs, we screened in silico the ZINC database using two different protocols involving structure- and ligand-based methodologies. Our search identified 19 novel low micromolar inhibitors of cultured chloroquine resistant P. falciparum. The most active compound presented an IC50 value of 0.5 μM against cultured parasites and it also inhibited the cysteine protease falcipain-2 (IC50 = 25.5 μM). These results identify novel classes of antimalarials that are structurally different from those currently in use and which can be further derivatized to deliver leads suitable for optimisation.
疟原虫对大多数现有药物的耐药性增加，给疟疾的控制带来了挑战。蛋白酶抑制剂的研究表明，裂殖体蛋白酶家族的半胱氨酸蛋白酶起着重要的作用。这些酶与其他蛋白酶协同作用，在寄生虫的食物泡中水解宿主红细胞血红蛋白。为了寻找潜在的新抗疟药物，我们使用两种不同的基于结构和基于配体的方法，在 ZINC 数据库中进行了计算机筛选。我们的搜索确定了 19 种新型低微摩尔氯喹耐药疟原虫培养物的抑制剂。最活跃的化合物对培养寄生虫的 IC50 值为 0.5 μM，对裂殖体蛋白酶 2（falcipain-2）也有抑制作用（IC50=25.5 μM）。这些结果确定了新型的抗疟药物类别，它们在结构上与目前使用的药物不同，可以进一步衍生出适合优化的先导化合物。
