title: 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.
abstract: 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.
authors.affiliation: Département de Toxicologie, Institut de Recherche Biomédicale des Armées, 24 Avenue des Maquis du Grésivaudan, BP87, 38702 La Tronche, France. florian@nachon.net
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
authors.forename: Eugénie
authors.initials: E
authors.lastname: Carletti
authors.forename: Cyril
authors.initials: C
authors.lastname: Ronco
authors.forename: Marie
authors.initials: M
authors.lastname: Trovaslet
authors.forename: Yvain
authors.initials: Y
authors.lastname: Nicolet
authors.forename: Ludovic
authors.initials: L
authors.lastname: Jean
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Renard
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology*; D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002802:Cholinesterases / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D018360:Crystallography, X-Ray / Q000379:methods*; D006801:Humans; D013619:Tacrine / Q000737:chemistry*
chemical_list: D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases