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Discovery, biological evaluation, and crystal structure of a novel nanomolar selective butyrylcholinesterase inhibitorBrus, Boris ...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 Ž1-42 peptide self-induced aggregation into fibrils (by 61.7% at 10 ŽM), and protected cultured SH-SY5Y cells against amyloid-Ž-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.Source: Journal of medicinal chemistry. - ISSN 0022-2623 (Vol. 57, issue 19, 2014, str. 8167-8179)Type of material - article, component partPublish date - 2014Language - englishCOBISS.SI-ID - 3713393
Author
Brus, Boris |
Košak, Urban |
Turk, Samo, farmacevt |
Pišlar, Anja |
Coquelle, Nicolas |
Kos, Janko, 1959- |
Stojan, Jure, 1956- |
Colletier, Jacques-Philippe |
Gobec, Stanislav, 1970-
Topics
Alzheimerʼs disease |
butyrylcholinesterase |
amyloid ß |
self induced Aß aggregation |
neuroprotection |
X ray crystallography |
structure based virtual screening
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Brus, Boris | 34508 |
Košak, Urban | 33908 |
Turk, Samo, farmacevt | 29773 |
Pišlar, Anja | 32035 |
Coquelle, Nicolas | |
Kos, Janko, 1959- | 04648 |
Stojan, Jure, 1956- | 03723 |
Colletier, Jacques-Philippe | |
Gobec, Stanislav, 1970- | 15284 |
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