Tyramine fragment binding to BACE-1

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• 作者：Andreas Kuglstatter ; Martin Stahl ; Jens-Uwe Peters ; Walter Huber ; Martine Stihle ; Daniel Schlatter ; Jö ; rg Benz ; Armin Ruf ; Doris Roth ; Thilo Enderle ; Michael Hennig
• 关键词：BACE-1 ; Alzheimer ; Fragment screening ; Surface plasmon resonance ; X-ray structure ; Structure-based design ; Tyramine
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：15 February 2008
• 年：2008
• 卷：18
• 期：4
• 页码：1304-1307
• 全文大小：731 K

文摘

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.