Selective tight binding inhibitors of trypanosomal glyceraldehyde-3-phosphate dehydrogenase via structure-based drug design
Selective tight binding inhibitors of trypanosomal glyceraldehyde-3-phosphate dehydrogenase via structure-based drug design
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DOI：
10.1021/jm9802620
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发表时间：
1998-11-19
影响因子：
7.3
通讯作者：
Gelb, MH
中科院分区：
文献类型：
--
作者：
Aronov, AM;Verlinde, CLMJ;Gelb, MH
来自昏睡病寄生虫布鲁氏锥虫的甘油醛-3-磷酸脱氢酶（GAPDH）是抗锥虫药物设计的合理目标，因为糖酵解为这种寄生虫的血流形式提供了几乎所有的能量。糖酵解也是其他致病性寄生虫的重要能量来源，包括克氏锥虫和墨西哥利什曼原虫。目前的研究是我们利用布鲁氏T.和墨西哥L.含有结合NAD（+）的GAPDHs的x射线结构来设计腺苷类似物的继续，这些类似物与容纳NAD（+）的腺苷部分的酶袋紧密结合。目的是提高先前报道的2'-脱氧-2'-（3-甲氧基苄胺）腺苷的亲和力、选择性和溶解度(1)。结果发现，在苯并胺环上引入羟基功能可以提高其溶解度，但不会显著影响酶的抑制作用。在先前未开发的嘌呤n -6位置的修饰不仅导致抑制剂效力的显着增加，而且还与糖的2'-苯并胺部分相容。对于n -6取代的腺苷，连续两轮建模和筛选提供了与腺苷相比330倍的亲和力。N-6-和2'-取代的组合产生了显著改善的抑制剂。1的n -6-苄基（9a）和n -6-2-甲基苄基（9b）衍生物对L. mexicana GAPDH的IC50值分别为16 μ M和4 μ M（比腺苷强3100倍和12500倍）。腺苷类似物不抑制人GAPDH。这些研究强调了基于结构的药物设计对于从弱结合先导化合物开始产生具有药用重要性的强效和物种选择性酶抑制剂的有用性。
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the sleeping sickness parasite Trypanosoma brucei is a rational target for anti-trypanosomatid drug design because glycolysis provides virtually all of the energy for the bloodstream form of this parasite. Glycolysis is also an important source of energy for other pathogenic parasites including Trypanosoma cruzi and Leishmania mexicana. The current study is a continuation of our efforts to use the X-ray structures of T. brucei and L. mexicana GAPDHs containing bound NAD(+) to design adenosine analogues that bind tightly to the enzyme pocket that accommodates the adenosyl moiety of NAD(+). The goal was to improve the affinity, selectivity, and solubility of previously reported 2'-deoxy-2'-(3-methoxybenzamido)adenosine (1). It was found that introduction of hydroxyl functions on the benzamido ring increases solubility without significantly affecting enzyme inhibition. Modifications at the previously unexploited N-6-position of the purine not only lead to a substantial increase in inhibitor potency but are also compatible with the 2'-benzamido moiety of the sugar. For N-6-substituted adenosines, two successive rounds of modeling and screening provided a 330-fold gain in affinity versus that of adenosine. The combination of N-6- and 2'-substitutions produced significantly improved inhibitors. N-6-Benzyl (9a) and N-6-2-methylbenzyl (9b) derivatives of 1 display IC50 values against L. mexicana GAPDH of 16 and 4 mu M, respectively (3100- and 12500-fold more potent than adenosine). The adenosine analogues did not inhibit human GAPDH. These studies underscore the usefulness of structure-based drug design for generating potent and species-selective enzyme inhibitors of medicinal importance starting from a weakly binding lead compound.