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
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