小说的恶性疟原虫亚精胺合成酶抑制剂:扭曲的尾巴。
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汉堡PB,威廉姆斯M,斯派格J, Reeksting某人,博塔M,穆勒IB, Joubert F, Birkholtz LM, Louw AI
小说的恶性疟原虫亚精胺合成酶抑制剂:扭曲的尾巴。
颧骨j . 2015年2月5日14:54。doi: 10.1186 / s12936 - 015 - 0572 - z。
- PubMed ID
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25651815 (在PubMed]
- 文摘
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背景:恶性疟原虫是最致病疟原虫物种和人类在非洲死亡的主要原因。抵抗大多数当前的新化疗药物强调了迫切的需求。聚胺代谢的寄生虫是不同于人类的途径为化疗发展成为一个有吸引力的目标。恶性疟原虫亚精胺合成酶(PfSpdS)催化亚精胺和精胺的合成。它是一个主要的聚胺flux-determining酶和亚精胺是翻译后激活的先决条件的恶性疟原虫真核翻译起始因子5 (elF5A)。最有效的抑制剂PfSpdS真核spd的不具体。方法:“动态”receptor-based药效团模型生成的晶体结构的spd发表与不同的配体。这种方法考虑了固有的活性部位的灵活性,从而减少与配体结合相关的处罚。四个动态药效团模型开发和两个抑制剂,(1 r, 4 r) - (N1 - (3-aminopropyl) -trans-cyclohexane-1 4-diamine(化合物8)和一个模拟,N - (3-aminopropyl)环己胺(化合物9),是确定的。结果:包含化合物的晶体结构解决了8和在网上证实了预测其aminopropyl链遍历的催化中心的存在催化的副产品,5 ' -methylthioadenosine。 The IC50 value of compound 9 is in the same range as that of the most potent inhibitors of PfSpdS, S-adenosyl-1,8-diamino-3-thio-octane (AdoDATO) and 4MCHA and 100-fold lower than that of compound 8. Compound 9 was originally identified as a mammalian spermine synthase inhibitor and does not inhibit mammalian SpdS. This implied that these two compounds bind in an orientation where their aminopropyl chains face the putrescine binding site in the presence of the substrate, decarboxylated S-adenosylmethionine. The higher binding affinity and lower receptor strain energy of compound 9 compared to compound 8 in the reversed orientation explained their different IC50 values. CONCLUSION: The specific inhibition of PfSpdS by compound 9 is enabled by its binding in the additional cavity normally occupied by spermidine when spermine is synthesized. This is the first time that a spermine synthase inhibitor is shown to inhibit PfSpdS, which provides new avenues to explore for the development of novel inhibitors of PfSpdS.