Interactions of pyridinium oximes with acetylcholinesterase

Catalytic activity of acetylcholinesterase (AChE; EC 3.1.1.7) was studied in the presence of oximes HI-6, K114, K127 and K203, and inhibition constants were determined for the reversible enzyme–inhibitor complex (KI). Based on the mixed inhibition model, inhibition constants were 0.020 mM for HI-6, 0.0021 mM for K114, 0.175 mM for K127, and 0.036 mM for K203. Molecular modelling of AChE–oxime complexes was used to determine amino acid residues of the active site involved in the interactions. Bis-oxime K114 achieved the best stabilization in the active site due to π–π interaction between its three aromatic rings and Tyr124, Tyr341 and Trp86, and hydrogen bonds formed by its oxime groups with Gly121 and Glu285. Mono-oximes HI-6 and K203, which inhibited the enzyme with similar potency, showed similar positions of their pyridinium rings in the active site. The weakest inhibitor, K127, also formed several hydrogen bonds with the active site residues, but due to its long linker it was more likely stabilized at the peripheral site (Tyr124), which could explain lower AChE affinity for this oxime.