5NN0
Crystal structure of huBChE with N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)-2-naphthamide.
Summary for 5NN0
| Entry DOI | 10.2210/pdb5nn0/pdb |
| Descriptor | Cholinesterase, 2-(2-{2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHANOL, DI(HYDROXYETHYL)ETHER, ... (12 entities in total) |
| Functional Keywords | butyrylcholinesterase ad alzheimer disease inhibitor, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 64494.69 |
| Authors | Coquelle, N.,Brus, B.,Colletier, J.P. (deposition date: 2017-04-07, release date: 2018-03-14, Last modification date: 2024-11-06) |
| Primary citation | Kosak, U.,Brus, B.,Knez, D.,Zakelj, S.,Trontelj, J.,Pislar, A.,Sink, R.,Jukic, M.,Zivin, M.,Podkowa, A.,Nachon, F.,Brazzolotto, X.,Stojan, J.,Kos, J.,Coquelle, N.,Salat, K.,Colletier, J.P.,Gobec, S. The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity. J. Med. Chem., 61:119-139, 2018 Cited by PubMed Abstract: The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-π interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease. PubMed: 29227101DOI: 10.1021/acs.jmedchem.7b01086 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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