A Computational Investigation of Small-Molecule Engagement of Hot Spots at Protein-Protein Interaction Interfaces.
A Computational Investigation of Small-Molecule Engagement of Hot Spots at Protein-Protein Interaction Interfaces.
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DOI：
10.1021/acs.jcim.7b00181
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发表时间：
2017-09-25
影响因子：
5.6
通讯作者：
Meroueh SO
中科院分区：
文献类型：
--
作者：
Xu D;Si Y;Meroueh SO
在大结合界面 (> 1,000 Å2) 上发生的紧密蛋白质-蛋白质相互作用 (KD < 100 nM) 对于用小分子破坏来说非常具有挑战性。成功抑制紧密相互作用不仅需要与蛋白质受体的高亲和力结合，还需要有效模拟蛋白质配体的关键界面残基。在这里，我们探索模拟天然蛋白质配体的界面残基和结合特征的小分子是否可以丰富蛋白质-蛋白质紧密相互作用的小分子抑制剂的商业文库。我们的目标是尿激酶受体（uPAR）与其丝氨酸蛋白酶配体尿激酶（uPA）之间的高亲和力单位纳摩尔蛋白质-蛋白质相互作用。我们介绍了三种对与 uPAR 对接的小分子进行排序的方法：（i）一种新的指纹方法，用于识别模拟 uPA 配体与 uPAR 受体界面残基结合特征的化合物； (ii) 药效团方法来识别模拟 uPA 界面残基位置的小分子； (iii) 指纹图谱和药效团相结合的方法。 uPA配体模拟和uPAR受体界面残基结合模式的结合使用产生了具有新化学型的小分子，其抑制具有个位数微摩尔结合亲和力和优异的配体效率。我们采用按目录模拟的方法来探索结构-活性关系。我们还报告了广泛的研究，这些研究确定了一些最初的命中要么缺乏稳定性，要么具有硫醇反应性，要么具有氧化还原活性。这项工作表明，配体界面残基和结合模式的模拟可以成为克服商业文库局限性的有效策略，以识别小分子起点，以开发紧密蛋白质-蛋白质相互作用的有效抑制剂。
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. Successful inhibition of tight interactions requires not only high-affinity binding to the protein receptor, but also effective mimicry of critical interface residues of the protein ligand. Here, we explore whether small molecules that mimic the interface residues and the binding profile of the native protein ligand can enrich commercial libraries for small-molecule inhibitors of tight protein-protein interactions. We target the high-affinity single-digit nanomolar protein-protein interaction between the urokinase receptor (uPAR) and its serine proteinase ligand urokinase (uPA). We introduce three methods for rank-ordering small molecules docked to uPAR: (i) a new fingerprint approach to identify compounds that mimic the uPA ligand binding profile to uPAR receptor interface 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. The combined use of uPA ligand mimicry and binding pattern to uPAR receptor interface residues led to small molecules with new chemotypes that inhibited with single-digit micromolar binding affinities and excellent ligand efficiencies. We conducted an analog-by-catalog approach to explore structure-activity relationships. We also report the extensive studies that identified several of the initial hits as either lacking stability, were thiol reactive, or redox active. This work suggests that mimicry of the ligand interface residue and binding pattern can be an effective strategy to overcome limitations of commercial libraries to identify small-molecule starting points for the development of potent inhibitors of tight protein-protein interactions.
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影响因子：
5.6
作者：
Bottger, A;Bottger, V;Lane, DP
通讯作者：
Lane, DP
影响因子：
4.8
作者：
Ding, Jingzhen;Mooers, Blaine H. M.;Lin, Jialing
通讯作者：
Lin, Jialing
影响因子：
3
作者：
Feig, M;Onufriev, A;Brooks, CL
通讯作者：
Brooks, CL
影响因子：
7.3
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
通讯作者：
Kerns, Jeffrey K.
影响因子：
14.9
作者：
UniProt Consortium
通讯作者：
UniProt Consortium