Exploring Key Orientations at Protein-Protein Interfaces with Small Molecule Probes
Exploring Key Orientations at Protein-Protein Interfaces with Small Molecule Probes
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DOI：
10.1021/ja3067258
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发表时间：
2013-01-09
影响因子：
15
通讯作者：
Burgess, Kevin
中科院分区：
文献类型：
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作者：
Ko, Eunhwa;Raghuraman, Arjun;Burgess, Kevin
选择性干扰蛋白质相互作用（PPI）的小分子探针对于生物医学至关重要，但它们的发现具有挑战性。我们假设表达氨基酸侧链与 PPI 界面区域的半刚性支架的构象相似性可以指导这一过程。因此，开发了一种数据挖掘算法来对大量 PPI 进行采样，以找到与所选半刚性支架的首选构象异构体相匹配的 PPI。一种此类化学型（laaa；全甲基侧链）的构象与几种具有生物医学意义的 PPI 相匹配，包括 HIV-1 蛋白酶的二聚化界面。在这些观察的基础上，制备了四种分子1，其侧链对应于匹配的HIV-1二聚化界面区域；所有四种药物均通过扰动二聚化来抑制 HIV-1 蛋白酶。这些数据表明，这种方法可能会激发小分子界面探针的设计，以干扰 PPI。
Small molecule probes that selectively perturb protein protein interactions (PPIs) are pivotal to biomedical science, but their discovery is challenging. We hypothesized that conformational resemblance of semirigid scaffolds expressing amino acid side-chains to PPI-interface regions could guide this process. Consequently, a data mining algorithm was developed to sample huge numbers of PPIs to find ones that match preferred conformers of a selected semirigid scaffold. Conformations of one such chemotype (laaa; all methyl side-chains) matched several biomedically significant PPIs, including the dimerization interface of HIV-1 protease. On the basis of these observations, four molecules 1 with side-chains corresponding to the matching HIV-1 dimerization interface regions were prepared; all four inhibited HIV-1 protease via perturbation of dimerization. These data indicate this approach may inspire design of small molecule interface probes to perturb PPIs.