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Interactions of chiral quinuclidin‐3‐yl benzoates with butyrylcholinesterase: kinetic study and docking simulations
Author(s) -
Primožič Ines,
Hrenar Tomica,
Tomić Srđanka,
Meić Zlatko
Publication year - 2002
Publication title -
journal of physical organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.325
H-Index - 66
eISSN - 1099-1395
pISSN - 0894-3230
DOI - 10.1002/poc.494
Subject(s) - chemistry , butyrylcholinesterase , enantiomer , hydrolysis , autodock , enzyme kinetics , stereochemistry , moiety , docking (animal) , kinetic resolution , medicinal chemistry , stereoselectivity , kinetics , indole test , active site , organic chemistry , enantioselective synthesis , enzyme , acetylcholinesterase , catalysis , biochemistry , nursing , quantum mechanics , in silico , gene , medicine , aché , physics
Both enantiomers of quinuclidin‐3‐yl benzoate (RQBz and SQBz) were synthesized in order to examine the stereoselectivity of the hydrolysis of these esters catalyzed by horse serum butyrylcholinesterase (BChE). The hydrolysis of benzoylcholine (BzCh) was also studied in order to determine the influence of the alcohol part of the esters upon the kinetics. The k cat value for the substrates decreased in order BzCh > RQBz (4‐fold slower) ≫SQBz (76‐fold slower reaction). K M values determined for quinuclidinium substrates revealed that the binding affinity of RQBz (0.28 m M ) is approximately 2‐fold lower than that of SQBz (0.13 m M ) towards BChE. From the ratio of the enantiomeric k cat / K M values, an enantiomeric excess of 78% was calculated, indicating that the resolution of racemic quinuclidin‐3‐yl benzoate can be achieved by hydrolysis with BChE. The orientations of all the studied benzoate esters and butyrylcholine (BuCh) in the active site of human BChE were proposed by flexible ligand docking with AutoDock 3.0. Analyses of the Michaelis complexes obtained revealed that there are numerous similar close contacts in the active site. The main difference in binding of quinuclidinium and choline esters was found in the ammonium electrostatic region which includes cation–π interaction of the ammonium moiety of substrates with the indole ring of Trp 84 . The important cation–π interaction with Trp 84 was lowest in the case of the S ‐enantiomer of QBz, which might be the main explanation for the slowest rate of hydrolysis of that compound. Copyright © 2002 John Wiley & Sons, Ltd.