The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesterase) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, π-π/cation-π interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. Huprine W forms additional interactions with hAChE, which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine residue and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE that is able to accommodate the chlorine substituent.
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Research Article|
July 12 2013
Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase
Florian Nachon;
Florian Nachon
1
*Département de Toxicologie, Institut de Recherche Biomédicale des Armées, 24 Avenue des Maquis du Grésivaudan, BP87, 38702 La Tronche, France
1To whom correspondence should be addressed (email florian@nachon.net).
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Eugénie Carletti;
Eugénie Carletti
*Département de Toxicologie, Institut de Recherche Biomédicale des Armées, 24 Avenue des Maquis du Grésivaudan, BP87, 38702 La Tronche, France
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Cyril Ronco;
Cyril Ronco
†Normandie Université, COBRA, UMR 6014 and FR 3038; Université Rouen, INSA Rouen; CNRS, 1 rue Tesnière, 76821 Mont-Saint-Aignan, Cedex, France
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Marie Trovaslet;
Marie Trovaslet
*Département de Toxicologie, Institut de Recherche Biomédicale des Armées, 24 Avenue des Maquis du Grésivaudan, BP87, 38702 La Tronche, France
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Yvain Nicolet;
Yvain Nicolet
‡Laboratoire de Cristallographie et Cristallogenèse des Protéines, Institut de Biologie Structurale ‘J.P. Ebel’, CEA, CNRS, Université Joseph Fourier, 41 rue J. Horowitz, 38027 Grenoble, France
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Ludovic Jean;
Ludovic Jean
†Normandie Université, COBRA, UMR 6014 and FR 3038; Université Rouen, INSA Rouen; CNRS, 1 rue Tesnière, 76821 Mont-Saint-Aignan, Cedex, France
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Pierre-Yves Renard
Pierre-Yves Renard
†Normandie Université, COBRA, UMR 6014 and FR 3038; Université Rouen, INSA Rouen; CNRS, 1 rue Tesnière, 76821 Mont-Saint-Aignan, Cedex, France
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Publisher: Portland Press Ltd
Received:
January 02 2013
Revision Received:
May 15 2013
Accepted:
May 17 2013
Accepted Manuscript online:
May 17 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 453 (3): 393–399.
Article history
Received:
January 02 2013
Revision Received:
May 15 2013
Accepted:
May 17 2013
Accepted Manuscript online:
May 17 2013
Citation
Florian Nachon, Eugénie Carletti, Cyril Ronco, Marie Trovaslet, Yvain Nicolet, Ludovic Jean, Pierre-Yves Renard; Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase. Biochem J 1 August 2013; 453 (3): 393–399. doi: https://doi.org/10.1042/BJ20130013
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