Chemical Space Overlap with Critical Protein-Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries.
Chemical Space Overlap with Critical Protein-Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries.
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商业和专业小分子文库中的化学空间与关键蛋白质-蛋白质界面残基重叠。
DOI：
10.1002/cmdc.201800537
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发表时间：
2019
期刊：
影响因子：
3.4
通讯作者：
Meroueh,SamyO
中科院分区：
文献类型：
--
作者：
Si,Yubing;Xu,David;Bum-Erdene,Khuchtumur;Ghozayel,MonaK;Yang,Baocheng;Clemons,PaulA;Meroueh,SamyO
人们对使用基于结构的虚拟筛选来识别抑制具有挑战性的蛋白质-蛋白质相互作用（PPIs）的小分子越来越感兴趣。在这项研究中，我们研究了停靠在PPI界面的化学文库成员如何有效地模拟被称为“热点”的关键侧链残基的位置。我们考虑了三个化合物集合，一个是商业上可用的筛选集合（ChemDiv），一个是包含天然产物样小分子的多样性导向合成（DOS）化合物集合，以及一个使用已建立的反应构建的库（“基于直观数据组织的可筛选化学宇宙”，SCUBIDOO）。选择三种已鉴定出热点残基的紧密ppi进行分析：uPAR⋅uPA、TEAD4⋅Yap1和cava α⋅CaVβ。对文库的理化性质进行分析，然后与PPI受体对接。药效团法用于测量小分子取代基和热点侧链之间的重叠。片段状构象受限小分子在具有明确口袋（如uPAR⋅uPA）的界面上表现出更好的热点重叠，而在缺乏明确结合位点（如TEAD4⋅Yap1）的界面上，更复杂的DOS化合物表现出更好的重叠。针对uPAR⋅uPA和TEAD4⋅Yap1的构象限制化合物的虚拟筛选和实验验证强化了这些发现，因为前者的最佳命中点是片段状的，并且具有很少的可旋转键，而后者没有发现命中点。总的来说，这些研究为在附加化学物质和新的PPI定义的背景下理解PPI提供了一个框架。
There is growing interest in the use of structure‐based virtual screening to identify small molecules that inhibit challenging protein–protein interactions (PPIs). In this study, we investigated how effectively chemical library members docked at the PPI interface mimic the position of critical side‐chain residues known as “hot spots”. Three compound collections were considered, a commercially available screening collection (ChemDiv), a collection of diversity‐oriented synthesis (DOS) compounds that contains natural‐product‐like small molecules, and a library constructed using established reactions (the “screenable chemical universe based on intuitive data organization”, SCUBIDOO). Three different tight PPIs for which hot‐spot residues have been identified were selected for analysis: uPAR⋅uPA, TEAD4⋅Yap1, and CaVα⋅CaVβ. Analysis of library physicochemical properties was followed by docking to the PPI receptors. A pharmacophore method was used to measure overlap between small‐molecule substituents and hot‐spot side chains. Fragment‐like conformationally restricted small molecules showed better hot‐spot overlap for interfaces with well‐defined pockets such as uPAR⋅uPA, whereas better overlap was observed for more complex DOS compounds in interfaces lacking a well‐defined binding site such as TEAD4⋅Yap1. Virtual screening of conformationally restricted compounds targeting uPAR⋅uPA and TEAD4⋅Yap1 followed by experimental validation reinforce these findings, as the best hits were fragment‐like and had few rotatable bonds for the former, while no hits were identified for the latter. Overall, such studies provide a framework for understanding PPIs in the context of additional chemical matter and new PPI definitions.