Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase:: Elucidation of a novel binding mode for a 2-amino-N6-substituted adenosine
Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase:: Elucidation of a novel binding mode for a 2-amino-N6-substituted adenosine
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DOI：
10.1021/jm000287a
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发表时间：
2000-11-02
影响因子：
7.3
通讯作者：
Gelb, MH
中科院分区：
文献类型：
--
作者：
Bressi, JC;Choe, J;Gelb, MH
作为以结构为基础设计腺苷类似物作为治疗非洲锥虫病药物的项目的一部分，合成了N-6-，2-氨基-N-6-和N-2-取代腺苷类似物，并进行了测试，以建立抑制布氏锥虫糖体磷酸甘油酸激酶(PGK)、甘油醛-3-磷酸脱氢酶(GAPDH)和甘油-3-磷酸脱氢酶(GPDH)的构效关系。对寄生虫PGK、GAPDH和GPDH与其腺苷底物络合的X射线结构的评估使我们产生了一系列同时针对这三种酶的腺苷类似物。PGK对含2-氨基的NG取代类似物有一定的偏好。其中2-氨基-N-6-[2“-(对羟苯基)乙基]腺苷(46B)是腺苷的23倍，其IC50为130微米，而2-[[2”-(对羟苯基)乙基]氨基]腺苷(46C)对布氏毛滴虫PGK的抑制作用较弱，IC50为500微米。为了探索在一个分子中具有N-6和N-2取代基可能提供的相加效应的可能性，将这两个系列中最好的配体结合到N-6，N-2-二取代腺苷类似物中，得到N-6-(2“-苯乙基)-2-[(2”-苯乙基)氨基]腺苷(69)，作为布鲁氏毛滴虫PGK的30um抑制剂，其效力是腺苷模板的100倍。相反，当在1.0 mm下测试时，这些系列化合物对寄生GAPDH或GPDH的抑制率均不超过10-20%。T，Brucei PGK/46B络合物的3.0埃X射线结构显示，与先前确定的ADP结合模式相比，核苷类似物发生翻转，核糖部分采用SYN构象。使用QXP和SAS程序套件进行的分子对接实验重现了这种“翻转和旋转”的结合模式。
As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N-6-, 2-amino-N-6-, and N-2-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for NG-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N-6-[2 "-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 muM. 2-[[2 "-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 muM. To explore the potential of an additive effect that having the N-6 and N-2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N-6,N-2-disubstituted adenosine analogues to yield N-6-(2 " -phenylethyl)-2-[(2 " -phenylethyl)amino]adenosine (69) as a 30 muM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 Angstrom X-ray structure of a T, brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this "flipped and rotated" binding mode.