In vitro and in silico evaluation of fucosterol from Sargassum horridum as potential human acetylcholinesterase inhibitor

Abstract

The fucosterol has been reported numerous biological activities. In this study, the activity in vitro of the fucosterol from Sargassum horridum as potential human acetylcholinesterase inhibitor was evaluated. The structural identification was obtained by nuclear magnetic resonance (NMR) spectroscopy and based on experimental data, we combined docking and molecular dynamics simulations coupled to the Molecular-Mechanics-Generalized-Born-Surface-Area approach to evaluating the structural and energetic basis for the molecular recognition of fucosterol and neostigmine at the binding site of acetylcholinesterase (AChE). In addition, the Lineweaver-Burk plot showed the nature of a non-competitive inhibition. The maximum velocity (V) and the constant of Michaelis-Menten (K) estimated for fucosterol (0.006 µM) were 0.015 1/V (ΔA/h and 6.399 1/[ACh] mM, respectively. While, for neostigmine (0.14 µM), the V was 0.022 1/V (ΔA/h) and K of 6.726 1/[ACh] mM, these results showed a more effective inhibition by fucosterol respect to neostigmine. Structural analysis revealed that neostigmine reaches the AChE binding site reported elsewhere, whereas fucosterol can act as a no-competitive and competitive acetylcholinesterase inhibitor, in agree with kinetic enzymatic experiments. Binding free energy calculations revealed that fucosterol reaches the acetylcholinesterase binding site with higher affinity than neostigmine, which is according to experimental results. Whereas the per-residue decomposition free energy analysis let us identify crucial residues involved in the molecular recognition of ligands by AChE. Results corroborate the ability of theoretical methods to provide crucial information at the atomic level about energetic and structural differences in the binding interaction and affinity from fucosterol with AChE.

Deciphering Molecular Mechanism of the Neuropharmacological Action of Fucosterol through Integrated System Pharmacology and In Silico Analysis

“…However, AD pathology is accompanied by the cholinergic deficit, which could be compensated by the AChE inhibitor. Previous studies showing the inhibitory activity of fucosterol against AChE [12,28] and our molecular docking findings suggest that fucosterol could be a promising AChE inhibitor having clinical application in AD.…”

“…Evidence from the literatures supports its various biological activities, including antioxidant [6,7,8,9], anti-inflammatory [7,8,10,11,12,13], anticancer [14,15], antidiabetic [16], cholesterol homeostasis [17], cholesterol-lowering [18], antihyperlipidemic [19], hepatoprotective [6,20,21], immunostimulatory [22], antimicrobial [23], antiobesity [24,25], and antidepressant [26] potentials. Moreover, fucosterol exhibits inhibitory activity against acetyl- and butyryl-cholinesterase (AChE and BChE) [27,28] and β-secretase (an enzyme responsible for Aβ production, which is related to Alzheimer’s disease) [29]. Fucosterol also attenuated Aβ-induced neuronal death [27,30] and ameliorated cognitive impairment in the Aβ-induced neurotoxicity model of adult rats [30].…”

Neuroprotective Potentials of Marine Algae and Their Bioactive Metabolites: Pharmacological Insights and Therapeutic Advances

“…Another study also demonstrated anticholinesterase activity of fucosterol [ 85 ]. Enzyme kinetics and computational analysis indicated a non-competitive mode of acetylcholinesterase (AChE) inhibition of fucosterol [ 115 ].…”

Macroalgae as a Valuable Source of Naturally Occurring Bioactive Compounds for the Treatment of Alzheimer’s Disease

“…In a recent study, fucosterol isolated from Sargassum horridum demonstrated potent inhibition against AChE activity [49]. Kinetic studies revealed that fucosterol showed competitive and non-competitive inhibition due to its high binding affinity to AChE compared to neostigmine.…”