Discovery, Biological Evaluation, and Crystal Structure of a Novel Nanomolar Selective Butyrylcholinesterase Inhibitor

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• 作者：Boris Brus ; Urban Ko拧ak ; Samo Turk ; Anja Pi拧lar ; Nicolas Coquelle ; Janko Kos ; Jure Stojan ; Jacques-Philippe Colletier ; Stanislav Gobec
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：57
• 期：19
• 页码：8167-8179
• 全文大小：511K
• ISSN：1520-4804

文摘

Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer鈥檚 disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent, compound 1 (IC₅₀ = 21.3 nM), was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed, and a dissociation constant of 2.7 nM was determined for the most potent stereoisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved, revealing the binding mode and providing clues for potential optimization. Additionally, compound 1 inhibited amyloid 尾_1鈥?2 peptide self-induced aggregation into fibrils (by 61.7% at 10 渭M) and protected cultured SH-SY5Y cells against amyloid-尾-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit-to-lead follow-up in the drug-discovery process against Alzheimer鈥檚 disease.