engleski

Differences in Cholinesterases Affinities toward Chiral Quinuclidinium Compounds

Non-quaternary and N-benzyl quaternary chiral quinuclidinium esters1, 2 and amides3, 4 of pivalic, butyric and benzoic acid were evaluated as substrates and/or inhibitors of cholinesterases. Inhibitory effect of quinuclidinium amides on acetylcholinesterase (AChE from electric eel) and butyrylcholinesterase (BuChE form horse serum) were determined using a spectrophotometric method (Ellman’ s reagent) in a microplate assay.5 Hydrolysis kinetics of chiral esters (HPLC analysis, substrate: benzoylcholine) revealed that (R)-enantiomers of tested esters are much better substrates than (S)- enantiomers. On the other hand, (S)-enantiomers of esters and amides showed higher affinity toward ChEs except in the case of the butyric acid derivatives. In order to explain experimental data concerning activity of enantiomers, molecular docking simulations were performed using AutoDock 4.0 suite of programs1. We employed flexible ligand docking (Lamarckian Genetic Algorithm (LGA) search method) allowing all possible torsions in molecules. The results are compared with those for benzoyl choline and galanthamine. It was shown that enantiomeric preference of cholinesterases, as well as rates of hydrolysis, are governed primarily by electrostatic interactions and steric limitations and in the choline subsite. The differences in orientation and relative energies will be presented and discussed.

Cholinesterases ; chiral quinuclidinium compounds ; kinetic studies ; docking simulations

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