Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease.

Butyrylcholinesterase (BChE) is a serine esterase that plays a role in the detoxification of natural as well as synthetic ester-bond-containing compounds. Alterations in BChE activity are associated with a number of diseases. Cholinergic system abnormalities in particular are correlated with the formation of senile plaques in Alzheimer's disease (AD), and administration of cholinesterase inhibitors is a common therapeutic approach used to treat AD. Here, our aim was to study the interaction between BChE and fluoxetine. Molecular docking simulations revealed that fluoxetine penetrated deep into the active-site gorge of BChE and that it was engaged in stabilizing noncovalent interactions with multiple subsites. In substrate kinetic studies, the V_m, K_m, k_cat and k_cat/K_m values were found to be 20.59 ± 0.36 U mg^-1 protein, 194 ± 14 µM, 1.3 × 10⁸ s^-1 and 6.7 × 10⁵ µM^-1s^-1, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an IC₅₀ value of 104 µM and a K_i value of 36.3 ± 4.7 µM. Overall, both the low K_i value and the high number of BChE-fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although in vivo mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.

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