Quinoline binding site on malaria pigment crystal:: A rational pathway for antimalaria drug design
Quinoline binding site on malaria pigment crystal:: A rational pathway for antimalaria drug design
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DOI：
10.1021/cg025550i
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发表时间：
2002-11-01
影响因子：
3.8
通讯作者：
Leiserowitz, L
中科院分区：
文献类型：
--
作者：
Buller, R;Peterson, ML;Leiserowitz, L
人类疟疾是最引人注目的、重新出现的传染病之一，是由多种疟原虫寄生虫引起的。当疟原虫吸收人体红细胞中的血红蛋白时，血红素的副产物结晶成微米大小的疟原虫色素（疟原虫色素）。利用最近报道的粉末晶体结构测定的合成血红素（β-血红素），我们在这里描述了它的理论生长形式，并显示它是类似的习性和形式的天然血红素。有了这些信息，我们提出了一个非共价结合位点的喹啉药物家族的β-高铁血红素增长最快的方向的端面。这种吸附机制的晶体生长抑制方面进行检查，相对于一个，相对于维斯公布的数据。表面结合位点阐明了各种喹啉活性的差异，揭示了不同喹啉官能团的重要性。喹啉类化合物的分子手性和中心对称β-高铁血红素晶面的手性之间的相互作用进行了分析，在晶体生长抑制方面。我们还提出了一个分子异构的结晶积木，喹啉表面结合的影响，以及β-血红素晶体的成核和大小。
Human malaria, one of the most striking, reemerging infectious diseases, is caused by several types of Plasmodium parasites. As the parasite digests hemoglobin in human red blood cells, the heme byproduct crystallizes into micron-sized malaria-pigment (hemozoin). Making use of a recently reported powder-crystal structure determination of synthetic hemozoin (beta-hematin), we describe here its theoretical growth form and show it to be similar in habit and form to that of natural hemozoin. With this information, we propose a noncovalent binding site for the quinoline drug family at the end face of the fastest-growing direction of beta-hematin. This adsorption mechanism is examined in terms of crystal growth inhibition vis-a-vis published data. The surface binding site elucidates the difference in activity of various quinolines, revealing the importance of the different quinoline fanctionalities. The interplay between molecular chirality of quinolines and the chirality of centrosymmetric beta-hematin crystal faces is analyzed in terms of crystal growth inhibition. We additionally propose a molecular isomerism of the crystalline building blocks, with implications on quinoline surface binding, as well as on nucleation and size of beta-hematin crystals.