Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.
Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.
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DOI：
10.1021/ja810025g
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发表时间：
2009-04-22
影响因子：
15
通讯作者：
Boger DL
中科院分区：
文献类型：
--
作者：
Shaginian A;Whitby LR;Hong S;Hwang I;Farooqi B;Searcey M;Chen J;Vogt PK;Boger DL
- 描述了作为靶向蛋白质-蛋白质相互作用的小分子文库的组成部分的α-螺旋模拟文库的设计和液相合成。候选α-螺旋模拟物的迭代设计、合成和评价从先前的三芳基模板开始，并通过筛选抑制MDM 2/p53结合的设计来细化。在确定了化学和生物学上令人满意的设计并与学术合作者的筛选能力一致后，将相应的完整文库组装为20种化合物的400种混合物（20 × 20 × 20-混合物），其中添加的亚基被设计为模拟α-螺旋的天然存在的i，i+4，i+7氨基酸侧链的所有可能排列。使用溶液相合成方案制备文库（8000种化合物），该方案在确保其长期可用于筛选活动的规模上使用酸/碱液-液萃取进行纯化。筛选文库以抑制MDM 2/p53结合不仅鉴定了文库所基于的前导α-螺旋模拟物，而且还表明伴随使用这种综合文库的初始筛选结果的消化可以提供对相互作用性质的了解（例如，α-螺旋介导的蛋白质-蛋白质相互作用）并定义负责识别的关键残基及其特征。
-The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i+4, i+7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead α-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an α-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.
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影响因子：
15
作者：
Boger, DL;Goldberg, J;Cheresh, DA
通讯作者：
Cheresh, DA
影响因子：
2.7
作者：
Boger, DL;Ozer, RS;Andersson, CM
通讯作者：
Andersson, CM
影响因子：
2.7
作者：
Boger, DL;Chai, WY;Andersson, CM
通讯作者：
Andersson, CM
影响因子：
15
作者：
Cheng, S;Comer, DD;Boger, DL
通讯作者：
Boger, DL
影响因子：
2.7
作者：
Capps, KJ;Humiston, J;Boger, DL
通讯作者：
Boger, DL