Synthesis and Demonstration of the Biological Relevance of sp(3) -rich Scaffolds Distantly Related to Natural Product Frameworks.
Synthesis and Demonstration of the Biological Relevance of sp(3) -rich Scaffolds Distantly Related to Natural Product Frameworks.
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DOI：
10.1002/chem.201704169
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发表时间：
2017-10-26
期刊：
影响因子：
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通讯作者：
Nelson A
中科院分区：
文献类型：
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作者：
Foley DJ;Craven PGE;Collins PM;Doveston RG;Aimon A;Talon R;Churcher I;von Delft F;Marsden SP;Nelson A
化学空间的富有成效的探索是化学生物学和药物化学领域的一个持久挑战。天然产物具有生物学相关性，其框架促进了化学工具和药物的发现。描述了一种“自上而下”的合成方法，该方法能够将一系列复杂的桥连中间体以高步骤效率转化为 26 种富含 sp3 的不同支架。这些支架具有类似局部天然产物的特征，但与特定天然产物框架的关系较远。为了评估生物学相关性，制备了一组 52 个片段，并通过高通量晶体学针对两个蛋白质家族（ATAD2、BRD1 和 JMJD2D）的三个靶标进行筛选。在每种情况下，都鉴定出 3D 片段命中，这将作为配体发现的独特起点。这表明与天然产物关系较远的框架可以促进化学空间内新的生物学相关区域的发现。
The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top‐down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3‐rich scaffolds. The scaffolds have local natural product‐like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high‐throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.
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影响因子：
2.1
作者：
AMORESE, A;ARCADI, A;ORTAR, G
通讯作者：
ORTAR, G
影响因子：
5.6
作者：
Ertl, Peter;Roggo, Silvio;Schuffenhauer, Ansgar
通讯作者：
Schuffenhauer, Ansgar
DOI：
10.1107/s205979831700331x
发表时间：
2017-03-01
影响因子：
2.2
作者：
Collins, Patrick M.;Ng, Jia Tsing;von Delft, Frank
通讯作者：
von Delft, Frank
影响因子：
7.3
作者：
Brow, Dean G.;Bostrom, Jonas
通讯作者：
Bostrom, Jonas
影响因子：
21.8
作者：
通讯作者：
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