Identification and Characterization of Novel Small Molecules as Potent Inhibitors of the Plasmodial Calcium-Dependent Protein Kinase 1
Identification and Characterization of Novel Small Molecules as Potent Inhibitors of the Plasmodial Calcium-Dependent Protein Kinase 1
复制标题
DOI：
10.1021/bi9005122
复制
发表时间：
2009-07-14
期刊：
影响因子：
2.9
通讯作者：
Leroy, Didier
中科院分区：
文献类型：
--
作者：
Lemercier, Guillaume;Fernandez-Montalvan, Amaury;Leroy, Didier
疟疾仍然是世界许多地区的主要杀手。最近，公私伙伴关系的作用有所增加，促使学术和工业科学家在药物靶点验证和药物发现的早期阶段将其专业知识结合起来，以确定潜在的新药。需要鉴定和表征在寄生虫中显示高功效、低毒性和低诱导抗性倾向的新分子。在这种情况下，我们研究了PfCDPK1抑制的结构要求。这是一种在恶性疟原虫中表达的钙依赖性蛋白激酶，已被遗传学证实为生存所必需。已开发了初步筛选试验。总共测试了54000种化合物，产生了两个不同的纳摩尔小分子抑制剂化学系列。每个系列中最有效的成员通过酶和生物物理分析进一步表征。解离速率的激酶复合物被证明是区分这两个系列的关键参数。最后，基于同源性的激酶核心结构域的模型已经建立，这使得下一代抑制剂的合理设计。
Malaria remains a major killer in many parts of the World. Recently, there has been an increase in the role of public-private partnerships inciting academic and industrial scientists to merge their expertise in drug-target validation and in the early stage of drug discovery to identify potential new medicines. There is a need to identify and characterize new molecules showing high efficacy, low toxicity with low propensity to induce resistance in the parasite. In this context, we have studied the structural requirements of the inhibition of PfCDPK1. This is a calcium-dependent protein kinase expressed in Plasmodium falciparum, which has been genetically confirmed as essential for survival. A primary screening assay has been developed. A total of 54000 compounds were tested, yielding two distinct chemical series of nanomolar small molecule inhibitors. The most potent members of each series were further characterized through enzymatic and biophysical analyses. Dissociation rates of the inhibitor-kinase complexes were shown to be key parameters to differentiate both series. Finally, a homology-based model of the kinase core domain has been built which allows rational design of the next generation of inhibitors.