engleski

Interactions of benzoate esters with cholinesterase: kinetic study and docking simulations

Chiral (S)-quinuclidin-3-yl benzoate (SQBz) and (R)-quinuclidin-3-yl benzoate (RQBz) were prepared and interactions with cholinesterase were studied in order to determine the usefulness of a biocatalytic method for resolution of racemic esters of quinuclidin-3-ol. RQBz and SQBz, as well as benzoylcholine chloride (BzCh), were tested as substrates for serum butyrylcholinesterase (BChE, EC 3.1.1.8). It was shown that nonquaternized S and RQBz are poorer substrates for BChE than BzCh. In case of RQBz the reaction rate was 7-fold, while for SQBz 100-fold slower than for tested choline ester. (R)-enantiomer of quinuclidinyl esters was shown 18-fold preference for BChE over (S)-enantiomer. Thus, molecular modelling studies were undertaken in order to understand the observed differences of tested compounds in binding to BChE, as well as to predict possible structural changes to further improve selectivities. Conformational spaces of SQBz and RQBz were analyzed at semiempirical level and three stable conformers were found for each enantiomer. Stable conformers were optimized with the DFT quantum-chemical method using B3LYP functional and 6-31G* basis set. Docking simulations were performed using AutoDock 3.0 suite of programs1. We employed two types of calculations: rigid-body docking of all optimized conformers and flexible ligand docking allowing all torsions in molecules. Lamarckian Genetic Algorithm (LGA) search method was used in both simulations. The results are compared with those for BzCh. The difference in orientation and relative energies will be presented and discussed.

BChE; molecular docking; kinetic study; Autodock

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