Davies Douglas R, Mamat Bjorn, Magnusson Olafur T, Christensen Jeff, Haraldsson Magnus H, Mishra Rama, Pease Brian, Hansen Erik, Singh Jasbir, Zembower David, Kim Hidong, Kiselyov Alex S, Burgin Alex B, Gurney Mark E, Stewart Lance J
deCODE biostructures, Inc., 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA.
J Med Chem. 2009 Aug 13;52(15):4694-715. doi: 10.1021/jm900259h.
We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein-protein interaction surfaces for fragment binding. We screened the FOL library against leukotriene A4 hydrolase (LTA4H) by X-ray crystallography. A diverse set of fragments including derivatives of resveratrol, nicotinamide, and indole were identified as efficient ligands for LTA4H. These fragments were elaborated in a small number of synthetic cycles into potent inhibitors of LTA4H representing multiple novel chemotypes for modulating leukotriene biosynthesis. Analysis of the fragment-bound structures also showed that the fragments comprehensively recapitulated key chemical features and binding modes of several reported LTA4H inhibitors.
我们描述了一种用于基于结构的药物发现的新型片段库，称为生命片段（FOL）。FOL库包括生命的天然小分子、其衍生物以及联芳基蛋白质结构模拟物。片段的选择有助于研究蛋白质活性位点、变构结合位点以及片段结合的蛋白质-蛋白质相互作用表面。我们通过X射线晶体学针对白三烯A4水解酶（LTA4H）筛选了FOL库。鉴定出了多种片段，包括白藜芦醇、烟酰胺和吲哚的衍生物，它们是LTA4H的有效配体。这些片段经过少量合成循环后被优化为LTA4H的强效抑制剂，代表了多种用于调节白三烯生物合成的新型化学类型。对片段结合结构的分析还表明，这些片段全面概括了几种已报道的LTA4H抑制剂的关键化学特征和结合模式。
