化学
片段(逻辑)
化学空间
小分子
配体效率
干草堆
组合化学
背景(考古学)
活动站点
分子
药物发现
立体化学
计算生物学
配体(生物化学)
生物化学
酶
有机化学
算法
计算机科学
万维网
古生物学
受体
生物
作者
Janis Müller,Raphael Klein,Olga O. Tarkhanova,Anastasiia Gryniukova,Petro Borysko,Stefan Merkl,Moritz Ruf,Alexander Neumann,Marcus Gastreich,Yurii S. Moroz,G. Klebe,Serghei Glinca
标识
DOI:10.1021/acs.jmedchem.2c00813
摘要
Fragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and "undruggable" targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine's multibillion REAL Space was performed. A total of 93 molecules out of 106 selected compounds were successfully synthesized. Forty compounds were active in at least one validation assay with the most active follow-up having a 13,500-fold gain in affinity. Crystal structures for six of the most promising binders were rapidly obtained, verifying the binding mode. The overall success rate for this novel fragment-to-hit approach was 40%, accomplished in only 9 weeks. The results challenge the established fragment prescreening paradigm since the standard industrial filters for fragment hit identification in a thermal shift assay would have missed the initial fragments.
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