A Cobalt-Containing Compound as a Stronger Inhibitor than Galantamine to Inhibit Acetylcholinesterase Activity: A New Drug Candidate for Alzheimer’s Disease Treatment
Affiliations: [a]
Department of Biochemistry, Semnan University of Medical Sciences, Semnan, Iran
| [b]
Department of Inorganic Chemistry Semnan University, Semnan, Iran
| [c]
Department of Biology, Faculty of Science, University of Zanjan, Zanjan, Iran
| [d]
Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
Correspondence:
[*]
Corresponding authors: Ali Khaleghian, Department of Biochemistry, Semnan University of Medical Sciences, Semnan, Iran. E-mail: [email protected]; Zahra Moosavi-Nejad, Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, 1993893973 Tehran, Iran. E-mail: [email protected].
Abstract: Background:Acetylcholinesterase (AChE) regulates the transmission of neural messages by hydrolyzing acetylcholine in synaptic spaces. Objective:The effects of many AChE inhibitors have been evaluated in the treatment of Alzheimer’s disease, but the present study examined a synthetic complex containing cobalt (SC) for the first time in the field of enzyme activity to evaluate enzyme inhibitory function. Methods: Ellman’s test was applied. AChE function was assessed in the presence of SC through docking and molecular dynamics analyses. The second structure of AChE was studied through circular dichroism (CD) spectroscopy. Results:Several enzymatic methods were utilized for the kinetics of AChE, which indicated the non-Michaelis and positive homotropic behavior of AChE in the absence of inhibitors (Hill coefficient = 1.33). However, the existence of inhibitors did not eliminate this homotropic state, and even AChE had a more sigmoidal shape than the galantamine at the presence of SC. Based on the CD spectroscopy results, AChE structure changed in the existence of inhibitors and substrates. Bioinformatics analysis revealed SC bonding to the channel of active site AChE. The number of hydrogen bonds was such that the flexibility of the enzyme protein structure due to inhibitor binding reduced AChE function. Conclusion:The results reflected that AChE exhibited a non-Michaelis and positive homotropic behavior, leading to a more inhibitory effect on the SC than the galantamine. The positive homotropic behavior of AChE was intensified due to the alteration in AChE protein structure by binding SC to hydrophobic region in the active site pathway and impressing Trp84.
