Brus_2014_J.Med.Chem_57_8167

Reference

Title : Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor - Brus_2014_J.Med.Chem_57_8167
Author(s) : Brus B , Kosak U , Turk S , Pislar A , Coquelle N , Kos J , Stojan J , Colletier JP , Gobec S
Ref : Journal of Medicinal Chemistry , 57 :8167 , 2014
Abstract :

Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's 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 beta1-42 peptide self-induced aggregation into fibrils (by 61.7% at 10 muM) and protected cultured SH-SY5Y cells against amyloid-beta-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's disease.

PubMedSearch : Brus_2014_J.Med.Chem_57_8167
PubMedID: 25226236
Gene_locus related to this paper: human-BCHE

Related information

Inhibitor 3F9
Gene_locus 3F9    human-BCHE
Structure 3F9    human-BCHE    4TPK

Citations formats

Brus B, Kosak U, Turk S, Pislar A, Coquelle N, Kos J, Stojan J, Colletier JP, Gobec S (2014)
Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitor
Journal of Medicinal Chemistry 57 :8167

Brus B, Kosak U, Turk S, Pislar A, Coquelle N, Kos J, Stojan J, Colletier JP, Gobec S (2014)
Journal of Medicinal Chemistry 57 :8167