Acetylcholinesterase inhibitors are the mainstay of Alzheimer's disease treatments, despite having only shortterm symptomatic benefits and severe side effects. Selective butyrylcholinesterase inhibitors (BuChEIs) may be more effective treatments in late-stage Alzheimer's disease with fewer side effects. Virtual screening is a powerful tool for identifying potential inhibitors in large digital compound databases. This study used structure based virtual screening combined with physicochemical filtering to screen the InterBioScreen and Maybridge databases for novel selective BuChEIs. The workflow rapidly identified 22 potential hits in silico, resulting in the discovery of a human BuChEI with low-micromolar potency in vitro (IC50 2.4 mu M) and high selectivity for butyrylcholinesterase over acetylcholinesterase. The compound was a rapidly reversible BuChEI with mixed-model in vitro inhibition kinetics. The binding interactions were investigated using in silico molecular dynamics and by developing structure-activity relationships using nine analogues. The compound also displayed high permeability in an in vitro model of the blood-brain barrier.
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[1]
[Anonymous], 2013, Policy brief for heads of government
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Walter & Eliza Hall Inst Med Res, IG Royal Parade, Parkville, Vic 3052, Australia
Canc Therapeut CRC, Bundoora, Vic 3086, AustraliaWalter & Eliza Hall Inst Med Res, IG Royal Parade, Parkville, Vic 3052, Australia
Baell, Jonathan B.
Holloway, Georgina A.
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Walter & Eliza Hall Inst Med Res, IG Royal Parade, Parkville, Vic 3052, Australia
Canc Therapeut CRC, Bundoora, Vic 3086, AustraliaWalter & Eliza Hall Inst Med Res, IG Royal Parade, Parkville, Vic 3052, Australia
机构:
Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Brus, Boris
Kosak, Urban
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Kosak, Urban
Turk, Samo
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Turk, Samo
Pislar, Anja
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Pislar, Anja
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Coquelle, Nicolas
Kos, Janko
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Jozef Stefan Inst, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Kos, Janko
Stojan, Jure
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Univ Ljubljana, Fac Med, Inst Biochem, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Stojan, Jure
Colletier, Jacques-Philippe
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Univ Grenoble Alpes, IBS, F-38044 Grenoble, France
CNRS, IBS, F-38044 Grenoble, France
CEA, IBS, F-38044 Grenoble, FranceUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Colletier, Jacques-Philippe
Gobec, Stanislav
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
[6]
Copeland RA, 2013, EVALUATION OF ENZYME INHIBITORS IN DRUG DISCOVERY: A GUIDE FOR MEDICINAL CHEMISTS AND PHARMACOLOGISTS, 2ND EDITION, P1, DOI 10.1002/9781118540398
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Walter & Eliza Hall Inst Med Res, IG Royal Parade, Parkville, Vic 3052, Australia
Canc Therapeut CRC, Bundoora, Vic 3086, AustraliaWalter & Eliza Hall Inst Med Res, IG Royal Parade, Parkville, Vic 3052, Australia
Baell, Jonathan B.
Holloway, Georgina A.
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Walter & Eliza Hall Inst Med Res, IG Royal Parade, Parkville, Vic 3052, Australia
Canc Therapeut CRC, Bundoora, Vic 3086, AustraliaWalter & Eliza Hall Inst Med Res, IG Royal Parade, Parkville, Vic 3052, Australia
机构:
Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Brus, Boris
Kosak, Urban
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Kosak, Urban
Turk, Samo
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
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Pislar, Anja
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Pislar, Anja
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Coquelle, Nicolas
Kos, Janko
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Jozef Stefan Inst, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Kos, Janko
Stojan, Jure
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Univ Ljubljana, Fac Med, Inst Biochem, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Stojan, Jure
Colletier, Jacques-Philippe
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Univ Grenoble Alpes, IBS, F-38044 Grenoble, France
CNRS, IBS, F-38044 Grenoble, France
CEA, IBS, F-38044 Grenoble, FranceUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
Colletier, Jacques-Philippe
Gobec, Stanislav
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Univ Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, SloveniaUniv Ljubljana, Fac Pharm, Askerceva 7, Ljubljana 1000, Slovenia
[6]
Copeland RA, 2013, EVALUATION OF ENZYME INHIBITORS IN DRUG DISCOVERY: A GUIDE FOR MEDICINAL CHEMISTS AND PHARMACOLOGISTS, 2ND EDITION, P1, DOI 10.1002/9781118540398