Franke Lutz, Schwarz Oliver, Müller-Kuhrt Lutz, Hoernig Christina, Fischer Lutz, George Sven, Tanrikulu Yusuf, Schneider Petra, Werz Oliver, Steinhilber Dieter, Schneider Gisbert
Institut für Organische Chemie und Chemische Biologie/ZAFES, Johann Wolfgang Goethe-Universität, Siesmayerstrasse 70, D-60323 Frankfurt am Main, Germany.
J Med Chem. 2007 May 31;50(11):2640-6. doi: 10.1021/jm060655w. Epub 2007 Apr 27.
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.
对一个天然产物库和基于天然产物的组合文库进行虚拟筛选，以寻找人类5-脂氧合酶（5-LO）活性的潜在抑制剂。我们分两步采用了基于配体的连续方法。首先，使用拓扑药效团描述符（CATS 2D方法）进行相似性搜索，以实现骨架跳跃。从430种物质的虚拟命中列表中选择了18种化合物，这些化合物与43种已知的5-LO抑制剂中的至少一种具有共同的药效团特征，这些抑制剂用作查询结构。两种新的化学类型在基于细胞的5-LO活性测定中表现出显著活性。这两种最有效的分子用作第二轮虚拟筛选的种子结构。这次，通过不同的基于配体的虚拟筛选方法分析了一个聚焦的基于天然产物的组合文库。筛选候选物最终集中的最佳分子在完整细胞中有效抑制了5-LO活性，可能代表了一类新型的5-LO抑制剂。结果证明了基于天然产物的筛选文库在命中和先导结构鉴定方面的潜力。
