Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum.
Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum.
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DOI：
10.1021/ci100039k
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发表时间：
2010-05-24
影响因子：
5.6
通讯作者：
Bergman LW
中科院分区：
文献类型：
--
作者：
Kortagere S;Welsh WJ;Morrisey JM;Daly T;Ejigiri I;Sinnis P;Vaidya AB;Bergman LW
疟疾是大多数发展中国家的地方病，估计每年发生近5亿例。人们充分认识到，需要设计新一代抗疟药物，以对付抗药性最强的疟原虫。在这项研究中，我们希望开发形成疟疾寄生虫入侵机制的关键蛋白质的抑制剂。顶复门寄生虫侵入宿主细胞的一个关键特征是肌球蛋白A（MyoA）的羧基末端尾与肌球蛋白尾相互作用蛋白（MTIP）之间的相互作用。使用诺氏疟原虫MTIP和MyoA尾肽的共晶体结构作为基于杂合结构的虚拟筛选方法的输入，我们鉴定了一系列具有抑制MTIP-MyoA相互作用的潜力的小分子。在最初测试的15种化合物中，吡唑-脲化合物抑制恶性疟原虫生长，EC 50值为145 nM。我们筛选了另外51种属于同一化学类别的化合物，并鉴定了8种EC 50值小于400 nM的化合物。有趣的是，这些化合物似乎在寄生虫生命周期的几个阶段起作用，阻止生长和发育。本研究中鉴定的吡唑脲化合物可能是有效的抗疟药，因为它们竞争性抑制MTIP和MyoA之间的关键蛋白质-蛋白质相互作用，该相互作用负责疟原虫的滑行运动和侵袭特征。
Malaria is endemic in most developing countries, with nearly 500 million cases estimated to occur each year. The need to design a new generation of antimalarial drugs that can combat the most drug-resistant forms of the malarial parasite is well recognized. In this study, we wanted to develop inhibitors of key proteins that form the invasion machinery of the malarial parasite. A critical feature of host-cell invasion by apicomplexan parasites is the interaction between the carboxy terminal tail of myosin A (MyoA) and the myosin tail interacting protein (MTIP). Using the co-crystal structure of the Plasmodium knowlesi MTIP and the MyoA tail peptide as input to the hybrid structure-based virtual screening approach, we identified a series of small molecules as having the potential to inhibit MTIP-MyoA interactions. Of the initial fifteen compounds tested, a pyrazole-urea compound inhibited P. falciparum growth with an EC50 value of 145 nM. We screened an additional 51 compounds belonging to the same chemical class and identified eight compounds with EC50 values less than 400 nM. Interestingly, the compounds appeared to act at several stages of the parasite’s life cycle to block growth and development. The pyrazole-urea compounds identified in this study could be effective antimalarial agents because they competitively inhibit a key protein-protein interaction between MTIP and MyoA responsible for the gliding motility and invasive features of the malarial parasite.
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