Discovery and Structure–Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening
datasetposted on 13.07.2016, 00:00 by Satish N. Dighe, Girdhar Singh Deora, Eugenio De la Mora, Florian Nachon, Stephen Chan, Marie-Odile Parat, Xavier Brazzolotto, Benjamin P. Ross
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 atomic-level interactions and offers opportunities for further development of the series.
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PAMPA-BBB modelseriesCompound 16Selective Butyrylcholinesterase InhibitorStructure-Based Virtual Screening Structure-basedpermeabilityX-ray crystal structureRelationshipAlzheimerscreeningatomic-level interactionsBuChE inhibitorshuBuChE IC 50submicromolar inhibitoropportunity567 9810.443 μ M567 981 moleculeslate-stage