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A DNA‐Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition
ChemMedChem ( IF 3.6 ) Pub Date : 2018-06-01 , DOI: 10.1002/cmdc.201800193
Nicholas Favalli 1 , Stefan Biendl 1 , Marco Hartmann 1 , Jacopo Piazzi 2 , Filippo Sladojevich 3 , Susanne Gräslund 4, 5 , Peter J Brown 4 , Katja Näreoja 5 , Herwig Schüler 5 , Jörg Scheuermann 1 , Raphael Franzini 1, 6 , Dario Neri 1
Affiliation  

A DNA‐encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5‐bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a Kd value of 6 nm, while compounds with the same substituents on an equidistant but flexible l‐lysine scaffold showed 140‐fold lower affinity. A 18 nm tankyrase‐1 binder featured l‐lysine as linking moiety, while molecules based on d‐Lysine or (2S,4S)‐amino‐l‐proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries.

中文翻译:


基于常见支架结构的 DNA 编码化合物库揭示了配体几何形状对蛋白质识别的影响



通过七个中心支架与两组 343×492 构建块的组合反应,合成了包含 120 万种化合物的 DNA 编码化学库 (DECL)。通过亲和捕获进行文库筛选表明,对于某些目标蛋白,结构单元的化学性质主导了选择结果,而对于其他蛋白,中心支架也对配体亲和力做出了至关重要的贡献。基于 3,5-双(氨甲基)苯甲酸核心结构的分子被发现可以结合人血清白蛋白 Kd值为 6 nm ,而等距但灵活的L-赖氨酸支架上具有相同取代基的化合物显示出 140 ‐倍数较低的亲和力。 18 nm tankyrase-1 结合剂以l-赖氨酸作为连接部分,而基于d-赖氨酸或 ( 2S , 4S )-氨基-l-脯氨酸的分子未显示出与靶标的可检测结合。这项工作表明,使化学结构单元朝向蛋白质靶标的方向预先决定的中心支架可以提高编码文库的筛选效率。
更新日期:2018-06-01
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