Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening.
Identifieur interne : 001B18 ( PubMed/Corpus ); précédent : 001B17; suivant : 001B19Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening.
Auteurs : Satish N. Dighe ; Girdhar Singh Deora ; Eugenio De La Mora ; Florian Nachon ; Stephen Chan ; Marie-Odile Parat ; Xavier Brazzolotto ; Benjamin P. RossSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2016.
English descriptors
- KwdEn :
- Alzheimer Disease (drug therapy), Alzheimer Disease (metabolism), Butyrylcholinesterase (metabolism), Cholinesterase Inhibitors (chemical synthesis), Cholinesterase Inhibitors (chemistry), Cholinesterase Inhibitors (pharmacology), Dose-Response Relationship, Drug, Drug Discovery, Drug Evaluation, Preclinical, Humans, Models, Molecular, Molecular Structure, Structure-Activity Relationship.
- MESH :
- chemical , chemical synthesis : Cholinesterase Inhibitors.
- chemical , chemistry : Cholinesterase Inhibitors.
- chemical , metabolism : Butyrylcholinesterase.
- drug therapy : Alzheimer Disease.
- metabolism : Alzheimer Disease.
- chemical , pharmacology : Cholinesterase Inhibitors.
- Dose-Response Relationship, Drug, Drug Discovery, Drug Evaluation, Preclinical, Humans, Models, Molecular, Molecular Structure, Structure-Activity Relationship.
Abstract
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.
DOI: 10.1021/acs.jmedchem.6b00356
PubMed: 27405689
Links to Exploration step
pubmed:27405689Le document en format XML
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<front><div type="abstract" xml:lang="en">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.</div>
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