Mimicking Intermolecular Interactions of Tight Protein-Protein Complexes for Small-Molecule Antagonists.
Mimicking Intermolecular Interactions of Tight Protein-Protein Complexes for Small-Molecule Antagonists.
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模拟小分子拮抗剂的紧密蛋白质-蛋白质复合物的分子间相互作用。
DOI：
10.1002/cmdc.201700572
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发表时间：
2017-11-08
期刊：
影响因子：
3.4
通讯作者：
Meroueh SO
中科院分区：
文献类型：
--
作者：
Xu D;Bum-Erdene K;Si Y;Zhou D;Ghozayel MK;Meroueh SO
紧密的蛋白质-蛋白质相互作用(Kd<；100 nm)发生在一个大的结合界面(>；1,000ä2)上，用小分子破坏是非常有挑战性的。从历史上看，抑制蛋白质-蛋白质相互作用的小分子的设计一直专注于模拟界面蛋白质配体侧链的位置。在这里，我们探索模仿天然蛋白质配体与蛋白质受体残基的成对分子间相互作用，以丰富用于紧密蛋白质-蛋白质相互作用的小分子抑制剂的商业文库。我们使用尿激酶受体(UPAR)与其配体尿激酶(UPA)之间的高亲和力相互作用(Kd=1 nM)来测试我们的方法。我们介绍了三种对对接到uPAR的小分子进行排序的方法：(I)表示uPA与uPAR残基成对相互作用能量的新指纹方法；(Ii)识别模拟uPA界面残基位置的小分子的药效团方法；以及(Iii)指纹和药效团相结合的方法。我们的工作导致了具有新化学类型的小分子，这些小分子抑制了uPAR·uPA蛋白与个位数微摩尔IC50的紧密相互作用。我们还报告了广泛的工作，确定了几个命中要么缺乏稳定性，硫醇反应，或氧化还原活性。这项工作表明，模拟天然配体的结合轮廓和界面残基的位置可能是丰富紧密蛋白质-蛋白质相互作用小分子抑制剂商业文库的有效策略。我们探索了在尿激酶及其受体之间紧密的蛋白质-蛋白质相互作用中，天然蛋白质配体与蛋白质受体残基的成对分子间相互作用的模拟。我们使用指纹和药效团方法来比较天然配体和对接化合物的结合图谱。我们确定了几个具有新化学类型的小分子，这些小分子抑制了与个位数微摩尔IC50的紧密相互作用。
Tight protein-protein interactions (Kd < 100 nM) that occur over a large binding interface (> 1,000 Å2) are highly challenging to disrupt with small molecules. Historically, the design of small molecules to inhibit protein-protein interactions has focused on mimicking the position of interface protein ligand side chains. Here, we explore mimicry of the pairwise intermolecular interactions of the native protein ligand with residues of the protein receptor to enrich commercial libraries for small-molecule inhibitors of tight protein-protein interactions. We use the high-affinity interaction (Kd = 1 nM) between the urokinase receptor (uPAR) and its ligand urokinase (uPA) to test our methods. We introduce three methods for rank-ordering small molecules docked to uPAR: (i) a new fingerprint approach that represents uPA’s pairwise interaction energies with uPAR residues; (ii) a pharmacophore approach to identify small molecules that mimic the position of uPA interface residues; and (iii) a combined fingerprint and pharmacophore approach. Our work led to small molecules with novel chemotypes that inhibited a tight uPAR•uPA protein-protein interaction with single-digit micromolar IC50s. We also report the extensive work that identified several of the hits as either lacking stability, thiol reactive, or redox active. This work suggests that mimicking the binding profile of the native ligand and the position of interface residues can be an effective strategy to enrich commercial libraries for small-molecule inhibitors of tight protein-protein interactions. We explore mimicry of the pairwise intermolecular interactions of the native protein ligand with residues of the protein receptor in the tight protein-protein interaction between urokinase and its receptor. We use both fingerprint and pharmacophore approaches to compare the binding profiles of the native ligand and docked compounds. We identify several small molecules with novel chemotypes that inhibited the tight interaction with single-digit micromolar IC50s.
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