Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease
Creators: name: Ozlem Dalmizrak
name: Teralı, Kerem
name: Yetkin, Osman
name: I. Hamdi Ogus
name: Ozer, Nazmi
Publisher: name: Taylor & Francis
Year: 2018
Subjects: subject: Biochemistry
subject: Neuroscience
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Ecology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: Cancer
subject: 111714 Mental Health
subject: FOS: Health sciences
subject: FOS: Health sciences
subject: Hematology
subject: 60506 Virology

description: 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 <i>V</i><sub>m</sub>, <i>K</i><sub>m</sub>, <i>k</i><sub>cat</sub> and <i>k</i><sub>cat</sub>/<i>K</i><sub>m</sub> values were found to be 20.59 ± 0.36 U mg<sup>−1</sup> protein, 194 ± 14 µM, 1.3 × 10<sup>8</sup> s<sup>−1</sup> and 6.7 × 10<sup>5</sup> µM<sup>−1</sup>s<sup>−1</sup>, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an <i>IC</i><sub>50</sub> value of 104 µM and a <i>K</i><sub>i</sub> value of 36.3 ± 4.7 µM.Overall, both the low <i>K</i><sub>i</sub> value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although <i>in vivo</i> mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated. 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 <i>V</i><sub>m</sub>, <i>K</i><sub>m</sub>, <i>k</i><sub>cat</sub> and <i>k</i><sub>cat</sub>/<i>K</i><sub>m</sub> values were found to be 20.59 ± 0.36 U mg<sup>−1</sup> protein, 194 ± 14 µM, 1.3 × 10<sup>8</sup> s<sup>−1</sup> and 6.7 × 10<sup>5</sup> µM<sup>−1</sup>s<sup>−1</sup>, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an <i>IC</i><sub>50</sub> value of 104 µM and a <i>K</i><sub>i</sub> value of 36.3 ± 4.7 µM. Overall, both the low <i>K</i><sub>i</sub> value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although <i>in vivo</i> mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.