6G1W

Crystal structure of Torpedo Californica acetylcholinesterase in complex with 2-{1-[2-(6-Chloro-1,2,3,4-tetrahydroacridin-9-ylamino)ethyl]-1H-1,2,3-triazol-4-yl}-N-[4-(hydroxy)-3-methoxybenzyl]acetamide

Replaces:  6FOV

Summary for 6G1W

• Entry DOI: 10.2210/pdb6g1w/pdb
• Descriptor: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-[1-[2-[(3-chloranylacridin-9-yl)amino]ethyl]-1,2,3-triazol-4-yl]-~{N}-[(3-methoxy-4-oxidanyl-phenyl)methyl]ethanamide, ... (5 entities in total)
• Functional Keywords: torpedo californica acetylcholinesterase, ad, alzheimer disease, hydrolase
• Biological source: Tetronarce californica (Pacific electric ray)
• Total number of polymer chains: 2
• Total formula weight: 130066.40

Authors

Coquelle, N.,Colletier, J.P. (deposition date: 2018-03-22, release date: 2018-04-04, Last modification date: 2024-01-17)

Primary citation

Galdeano, C.,Coquelle, N.,Cieslikiewicz-Bouet, M.,Bartolini, M.,Perez, B.,Clos, M.V.,Silman, I.,Jean, L.,Colletier, J.P.,Renard, P.Y.,Munoz-Torrero, D.
Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis.
Molecules, 23:-, 2018

PubMed Abstract: Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.

PubMed: 29534488
DOI: 10.3390/molecules23030634

Experimental method

X-RAY DIFFRACTION (1.9 Å)