INHIBITORS OF PLASMODIUM FALCIPARUM ALDOLASE STUDIED BY X-RAY CRYSTALLOGRAPHY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 Bosch实验室对能够使疟疾寄生虫恶性疟原虫侵入或逃离人类肝脏和红细胞以及Moscovirus载体中肠细胞的蛋白质感兴趣。通过基于结构的药物设计与X射线晶体学相结合，我们试图识别和优化小分子，这些小分子将抑制关键酶的功能及其与重要伴侣蛋白的相互作用，从而削弱寄生虫的增殖能力。通过虚拟文库化合物筛选，我们已经发现了对恶性疟原虫醛缩酶具有特异性的有希望的候选化合物。在尝试共结晶之前，对60种低分子量化合物的子集进行了酶促和生物药理学表征。同时，我们获得了与醛缩酶预期区域结合的三个配体的结构，并正在与这些初始命中的衍生物进行进一步的构效关系研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Bosch lab is interested in proteins enabling the malaria parasite Plasmodium falciparum to invade or escape from human liver- and red blood cells as well as Mosquito vector midgut cells. By structure based drug design in conjunction with X-ray crystallography, we seek to identify and optimize small molecules which will inhibit the functions of key enzymes and their interaction with essential partner proteins, thus impairing the parasite's ability to proliferate. Through virtual library compound screening, we already found promising candidates specific for P. falciparum Aldolase. A subset of 60 low molecular weight compounds was enzymatically and biophysically characterized, before attempting co-crystallization. Meanwhile, we obtained structures of three ligands bound to the expected region of Aldolase and are pursuing further structure activity relationship studies with derivatives of those initial hits.