期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 8, 页码 2543-2549出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm801657v
关键词
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资金
- Divadol Foundation
- Israel Science Foundation
- Nalvyco Foundation
- Neuman Foundation
- Bruce Rosen Foundation
- Jean and Jula Goldwurm Memorial Foundation
- Benoziyo Center for Neuroscience
- European Commission Sixth Framework Research and Technological Development Programme [LSHG-CT-2006-031220]
- Teach-SG [ISSG-CT-2007-037198]
- National Natural Science Foundation of P.R. China [30472088, 30772553]
- ECUST
- Morton and Gladys Pickman Professor of Structural Biology
A bis-(-)-nor-meptazinol derivative in which the two meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and A beta peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 angstrom resolution. The ligand spans the active-site gorge, with one nor-meptazinol moiety bound at the anionic subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440N(epsilon 2), which is hydrogen-bonded to Ser2000(gamma) in the native enzyme. The second nor-meptazinol binds at the peripheral anionic site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(-)-nor-meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new meptazinol-based acetylcholinesterase inhibitors.
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