Identification of natural-product-derived inhibitors of 5-lipoxygenase activity by ligand-based virtual screening
Identification of natural-product-derived inhibitors of 5-lipoxygenase activity by ligand-based virtual screening
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DOI：
10.1021/jm060655w
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发表时间：
2007-05-31
影响因子：
7.3
通讯作者：
Schneider, Gisbert
中科院分区：
文献类型：
--
作者：
Franke, Lutz;Schwarz, Oliver;Schneider, Gisbert
一个天然产物的集合和天然产物衍生的组合库，几乎筛选潜在的抑制剂的人5-脂氧合酶（5-LO）的活动。我们遵循基于配体的连续方法分两步进行。首先，使用拓扑药效团描述符（CATS 2D方法）进行相似性搜索以实现支架跳跃。从430种物质的虚拟命中列表中选择了18种化合物，这些物质与作为查询结构的43种已知5-LO抑制剂中的至少一种具有相互药效团特征。两个新的化学型在基于细胞的5-LO活性测定中表现出显着的活性。两个最有效的分子作为种子结构进行第二轮虚拟筛选。这一次，通过不同的基于配体的虚拟筛选方法分析了一个集中的天然产物衍生的组合文库。最好的分子从最终的筛选候选人有效地抑制5-LO活性在完整的细胞，并可能代表一类新的5-LO抑制剂。结果表明，潜在的天然产物衍生的筛选库命中和铅结构鉴定。
A natural product collection and natural-product-derived combinatorial libraries were virtually screened for potential inhibitors of human 5-lipoxygenase (5-LO) activity. We followed a sequential ligand-based approach in two steps. First, similarity searching with a topological pharmacophore descriptor (CATS 2D method) was performed to enable scaffold-hopping. Eighteen compounds were selected from a virtual hit list of 430 substances, which had mutual pharmacophore features with at least one of 43 known 5-LO inhibitors that served as query structures. Two new chemotypes exhibited significant activity in a cell-based 5-LO activity assay. The two most potent molecules served as seed structures for a second virtual screening round. This time, a focused natural-product-derived combinatorial library was analyzed by different ligand-based virtual screening methods. The best molecules from the final set of screening candidates potently suppressed 5-LO activity in intact cells and may represent a novel class of 5-LO inhibitors. The results demonstrate the potential of natural-product-derived screening libraries for hit and lead structure identification.