Discovery and Structure−Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening

Satish N. Dighe, Girdhar Singh Deora, Eugenio De La Mora, Florian Nachon, Stephen Chan, Marie-Odile Parat, Xavier Brazzolotto, Benjamin P. Ross

Research output: Contribution to journalArticleResearchpeer-review

77 Citations (Scopus)

Abstract

Structure-based virtual screening of two libraries containing 567 981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 was identified as a highly selective submicromolar inhibitor of BuChE (huBuChE IC50 = 0.443 μM) with high permeability in the PAMPA-BBB model. The X-ray crystal structure of huBuChE in complex with 16 revealed the atomiclevel interactions and offers opportunities for further development of the series.

Original languageEnglish
Pages (from-to)7683-7689
Number of pages7
JournalJournal of Medicinal Chemistry
Volume59
Issue number16
DOIs
Publication statusPublished - 25 Aug 2016
Externally publishedYes

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