Interactions of Monoquaternary Pyridinium Oximes with Acetylcholinesterase: A Docking Study

Monoquaternary N-benzyl-4-hydroxyiminomethylpyridinium bromide (Py-4-H) and its analogous with diverse substituents introduced into the phenyl ring (Py-4-CH3, Py-4-Br, Py-4-Cl and Py-4-NO2) were previously evaluated as inhibitors of human erythrocyte acetylcholinesterase (AChE ; EC 3.1.1.7) as well as reactivators of tabun-inhibited AChE (Z. Kovarik et al.). Therefore, we performed docking studies to elucidate the differences in oximes potency. The orientations of all studied oximes in the active site of human AChE have been proposed by flexible ligand docking with AutoDock 3.0. Two forms of each oxime - protonated (=NOH) and deprotonated (=NO-) oxime group - were used for docking simulations. Analyses of the obtained complexes revealed the presence of numerous hydrogen bonds and close contacts between the oximes and the residues in the active site. It can be seen that ligands are oriented in such a way that the hydrogen bond is always formed between the oxime oxygen and various amino acids. Furthermore aromatic rings of the ligand are stabilized via the  - interactions mainly with Trp86, occupying in the most cases the choline binding site. Some clusters of geometries are found to be positioned toward the rim of the active site gorge making H-bonds with the Thr75 and Ser293 and  - interactions with some aromatic amino acids present in the active site gorge. The main difference in binding of Py-4-Br and Py-4-NO2 is in that region ; in the case of Py-4-Br there are much more clusters of geometries which is probably due to the size of that ligand. For Py-4-H none of the clusters in that region were found. Final docked energies predicted correctly the relative order of the inhibition potency of compounds (experimentally: Py-4-Br < Py-4-Cl < Py-4-CH3 < Py-4-H < Py-4-NO2) except in the case of Py-4-CH3 which was determined as a second strongest inhibitor. For the best reactivator of tabun-inhibited AChE, Py-4-Br, the most probable orientation which can result in an attack on the phosphorus atom of the tabun-phosphorylated human AChE was proposed.