Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists.
Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists.
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DOI：
10.1371/journal.pone.0032839
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Camacho CJ
中科院分区：
文献类型：
--
作者：
Koes D;Khoury K;Huang Y;Wang W;Bista M;Popowicz GM;Wolf S;Holak TA;Dömling A;Camacho CJ
虽然并不缺乏潜在的药物靶点，但只有少数已知的蛋白质-蛋白质相互作用（PPI）的低分子量抑制剂。一个问题是，目前的努力主要是低产量的高通量筛选，其刚性框架不适合PPI中存在的不同化学型。在这里，我们开发了一种新的基于药效团的交互式筛选技术，该技术建立在PPI中的锚残基或深埋热点的作用上，并使用锚偏置虚拟多组分反应重新设计这些入口点，提供数千万种易于合成的新型化合物。将这种方法应用于MDM 2/p53癌症靶点导致高命中率，从而产生大量不同的确认抑制剂，并且共晶结构验证了所设计的化合物。我们独特的开放获取技术有望通过利用内部小规模测定和用户友好的化学方法来合理设计具有已知结构的PPI配体，从而扩大化学空间和人类相互作用组的探索。
Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure.
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影响因子：
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通讯作者：
Pasquale, Elena B.
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