Structure of acetylcholinesterase complexed with (−)‐galanthamine at 2.3 Å resolution

Abstract

(3 3)-Galanthamine (GAL), an alkaloid from the flower, the common snowdrop (Galanthus nivalis), shows anticholinesterase activity. This property has made GAL the target of research as to its effectiveness in the treatment of Alzheimer's disease. We have solved the X-ray crystal structure of GAL bound in the active site of Torpedo californica acetylcholinesterase (TcAChE) to 2.3 A î resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp-84) and the acyl-binding pocket (Phe-288, Phe-290). The tertiary amine group of GAL does not interact closely with Trp-84; rather, the double bond of its cyclohexene ring stacks against the indole ring. The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp-72, near the top of the gorge. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 A î ) with Glu-199. The relatively tight binding of GAL to TcAChE appears to arise from a number of moderate to weak interactions with the protein, coupled to a low entropy cost for binding due to the rigid nature of the inhibitor.z 1999 Federation of European Biochemical Societies.

New natural cholinesterase inhibiting and calcium channel blocking quinoline alkaloids

“…Since the discovery of physostigmine [10] as the first natural AChE inhibitor, only few other natural inhibitors have attracted the attention of neuropharmacologists [11]. We have previously reported a number of novel natural inhibitors of cholinesterases isolated from various medicinal plants [12 -18].…”

Design, synthesis, and biological evaluation of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives as novel acetylcholinesterase inhibitors

“…There are a lot of complex structures of Torpedo californica AChE (TcAChE) and mouse AChE with inhibitors determined experimentally, such as donepezil (PDB code: 1EVE), 7 tacrine (PDB code: 1ACJ), 8 gallamine (PDB code: 1N5M), 9 huperzine A (PDB code: 1VOT), 10 galanthamine (PDB code: 1DX6), 11 and obidoxime (PDB code: 2GYW). 12 All these structures significantly enhance our understanding of the structure of AChE.…”

Relevant activities of extracts and constituents of animals used in traditional Chinese medicine for central nervous system effects associated with Alzheimer's disease

“…The double bond, present in all active compounds, may have some interaction with the indole ring of AChE, since the double bond of galanthamine stacks with the indole ring of the enzyme (Greenblatt et al 1999). Since only fatty acids with more than 16 C atoms have an inhibitory effect on AChE, it may be that the enzyme has two ligand binding sites for these compounds, one being a peripheral site and the other the active site, at the bottom of the gorge, where interaction with the indole ring of tryptophan 84 occurs (Sussman et al 1991).…”