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Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach.
ChemMedChem ( IF 3.4 ) Pub Date : 2020-03-18 , DOI: 10.1002/cmdc.202000024
Markella Konstantinidou 1 , Francesca Magari 2 , Fandi Sutanto 1 , Jörg Haupenthal 3 , Varsha R Jumde 3, 4 , M Yagiz Ünver 3, 4 , Andreas Heine 2 , Carlos Jamie Camacho 5 , Anna K H Hirsch 3, 4, 6 , Gerhard Klebe 2 , Alexander Dömling 1
Affiliation  

Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one‐step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi‐valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one‐step. Next, we performed anchor‐based pharmacophore screening of the libraries and resynthesized top‐ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.

中文翻译:

使用锚定方法快速发现天冬氨酰蛋白酶抑制剂。

包含锚的药效学搜索,对受体结合贡献高于平均水平的片段,结合一步合成是快速发现新型生物活性分子的有力方法。在这里,我们展示了一条用于快速有效地发现天冬氨酰蛋白酶抑制剂的管道。首先,我们假设肼可能是与活性位点 Asp 羧酸相互作用的多价弹头。我们将肼锚定在多组分反应中,并创建了一个大型的肼衍生物虚拟库,可一步合成获得。接下来,我们对文库进行了基于锚定的药效团筛选,并重新合成了排名靠前的化合物。分子的抑制效力最终通过酶活性测定进行评估,结合模式由几种浸泡的晶体结构证实,支持假设和方法的有效性。本文报道的工具管道对于快速生成除 Asp 蛋白酶之外的受体结合剂具有普遍价值。
更新日期:2020-04-22
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