Kuglstatter Andreas, Stahl Martin, Peters Jens-Uwe, Huber Walter, Stihle Martine, Schlatter Daniel, Benz Jörg, Ruf Armin, Roth Doris, Enderle Thilo, Hennig Michael
F. Hoffmann-La Roche, Pharma Research Basel, Grenzacherstr., 4070 Basel, Switzerland.
Bioorg Med Chem Lett. 2008 Feb 15;18(4):1304-7. doi: 10.1016/j.bmcl.2008.01.032. Epub 2008 Jan 11.
Fragment screening revealed that tyramine binds to the active site of the Alzheimer's disease drug target BACE-1. Hit expansion by selection of compounds from the Roche compound library identified tyramine derivatives with improved binding affinities as monitored by surface plasmon resonance. X-ray structures show that the amine of the tyramine fragment hydrogen-bonds to the catalytic water molecule. Structure-guided ligand design led to the synthesis of further low molecular weight compounds that are starting points for chemical leads.
片段筛选显示，酪胺可与阿尔茨海默病药物靶点β-分泌酶1（BACE-1）的活性位点结合。通过从罗氏化合物库中选择化合物进行命中物扩展，鉴定出结合亲和力有所提高的酪胺衍生物，这通过表面等离子体共振进行监测。X射线结构表明，酪胺片段的胺与催化水分子形成氢键。基于结构的配体设计导致合成了进一步的低分子量化合物，这些化合物是化学先导物的起始点。
