Novel prostaglandin D synthase inhibitors generated by fragment-based drug design
Novel prostaglandin D synthase inhibitors generated by fragment-based drug design
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DOI：
10.1021/jm701509k
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发表时间：
2008-04-10
影响因子：
7.3
通讯作者：
Edman, Karl
中科院分区：
文献类型：
--
作者：
Hohwy, Morten;Spadola, Loredana;Edman, Karl
我们描述了通过基于片段的先导化合物生成和基于结构的药物设计发现新型前列腺素 D2 合酶 (PGDS) 抑制剂。使用 2D 核磁共振 (NMR) 筛选了 2500 种低分子量化合物的库，从而鉴定出 24 个主要化合物。通过命中的蛋白质-配体复合物的结构确定实现了命中优化过程，由此我们从我们的公司化合物集合中收获了越来越有效的抑制剂。进行了两个迭代循环，包括 NMR 筛选、分子建模、X 射线晶体学和体外生化测试。确定了六种新型高分辨率 PGDS 复合物结构，并测试了 300 个命中类似物。这种合理的药物设计程序最终在体外试验中发现了 24 种 IC50 低于 1 μM 的化合物。最好的抑制剂 (IC50 = 21 nM) 是迄今为止最有效的 PGDS 抑制剂之一。因此，它可能使 PGDS 和前列腺素代谢途径的新功能体内研究成为可能。
We describe the discovery of novel inhibitors of prostaglandin D2 synthase (PGDS) through fragment-based lead generation and structure-based drug design. A library of 2500 low-molecular-weight compounds was screened using 2D nuclear magnetic resonance (NMR), leading to the identification of 24 primary hits. Structure determination of protein-ligand complexes with the hits enabled a hit optimization process, whereby we harvested increasingly more potent inhibitors out of our corporate compound collection. Two iterative cycles were carried out, comprising NMR screening, molecular modeling, X-ray crystallography, and in vitro biochemical testing. Six novel high-resolution PGDS complex structures were determined, and 300 hit analogues were tested. This rational drug design procedure culminated in the discovery of 24 compounds with an IC50 below 1 mu M in the in vitro assay. The best inhibitor (IC50 = 21 nM) is one of the most potent inhibitors of PGDS to date. As such, it may enable new functional in vivo studies of PGDS and the prostaglandin metabolism pathway.