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.

Pub. Date : 2013 Aug 1

PMID : 23679855






4 Functional Relationships(s)
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1 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. huprine butyrylcholinesterase Homo sapiens
2 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 butyrylcholinesterase Homo sapiens
3 Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, pi-pi/cation-pi interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. huprine butyrylcholinesterase Homo sapiens
4 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. huprine butyrylcholinesterase Homo sapiens