Structure-based virtual screening of two libraries containing 567981 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 muM) 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.
Dighe SN, Deora GS, De la Mora E, Nachon F, Chan S, Parat MO, Brazzolotto X, Ross BP (2016) Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening Journal of Medicinal Chemistry59: 7683-9
Dighe SN, Deora GS, De la Mora E, Nachon F, Chan S, Parat MO, Brazzolotto X, Ross BP (2016) Journal of Medicinal Chemistry59: 7683-9