Molecular docking of different inhibitors and activators to butyrylcholinesterase

There are three major active sites of butyrylcholinesterase: catalytic site, peripheral site, and activator site. In this study, pseudosubstrate inhibitors, 1,3,5-alkylcarbamyloxybenzenes (1-11), were designed as the catalytic site directed inhibitors of the enzyme. Automated docking of 1,3,5-tri-n-octylcarbamyloxybenzene 1 into the X-ray crystal structure of butyrylcholinesterase suggested that the configuration of the inhibitor in the enzyme complex is in the (1,3,5)-(cis,trans,trans)-form. Thus, the cis n-octylcarbamyl group of 1 extended itself to the peripheral site; furthermore, two trans n-octylcarbamyl moieties of 1 shielded W82 of the anionic site. 5-N-n-Butylcarbamyloxyresorcinol (12) was further used to characterize the butyryl group binding site of the catalytic site. Automated docking of 12 into the enzyme showed that the best bound rotamer of the inhibitor in the enzyme complex was the trans form. Moreover, the butylcarbamyl moiety of 12 was bound well into the butyryl group binding site of the enzyme. Docking of cage amines into the enzyme indicated that these compounds were bound into the peripheral site of the enzyme. We also found that a small cave, located outside the enzyme around A277-Y282, might play an important role in the activation of the enzyme. Two activators of butyrylcholinesterase, n-butyl-N-carbamyloxy-3,3-dimethylbutane and 2,4,6-trinitrotoluene, were docked well into the above-mentioned cave.