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

Abstract

Fucosterol is an algae-derived unique phytosterol having several medicinal properties, including antioxidant, anti-inflammatory, anticholinesterase, neuroprotective, and so on. Accumulated evidence suggests a therapeutic promise of fucosterol in neurodegeneration; however, the in-depth pharmacological mechanism of its neuroprotection is poorly understood. Here, we employed system pharmacology and in silico analysis to elucidate the underlying mechanism of neuropharmacological action of fucosterol against neurodegenerative disorders (NDD). Network pharmacology revealed that fucosterol targets signaling molecules, receptors, enzymes, transporters, transcription factors, cytoskeletal, and various other proteins of cellular pathways, including tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), neurotrophin, and toll-like receptor (TLR) signaling, which are intimately associated with neuronal survival, immune response, and inflammation. Moreover, the molecular simulation study further verified that fucosterol exhibited a significant binding affinity to some of the vital targets, including liver X-receptor-beta (LXR-β), glucocorticoid receptor (GR), tropomyosin receptor kinase B (TrkB), toll-like receptor 2/4 (TLR2/4), and β-secretase (BACE1), which are the crucial regulators of molecular and cellular processes associated with NDD. Together, the present system pharmacology and in silico findings demonstrate that fucosterol might play a significant role in modulating NDD-pathobiology, supporting its therapeutic application for the prevention and treatment of NDD.

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

“…Fucosterol showed a potential anti-BACE1 activity, which was a noncompetitive type [ 134 ]. Supporting these findings, a recent in silico study also explained the binding and interaction pattern of fucosterol with BACE1 [ 142 ]. α-Bisabolol from Padina gymnospora prevented oligomers formation as well as disaggregated the matured fibrils [ 118 ].…”

“…This approach is also known as target fishing, which identifies not only interacting proteins but also potential off-targets, and thus helps to understand polypharmacology, pharmacokinetics, and toxicity in the early stages of drug discovery [ 240 ]. For example, using in silico target fishing approach, Hannan and colleagues elucidated pharmacological mechanism of fucosterol-mediated neuroprotection and demonstrated that fucosterol showed interaction with potential targets, including LXR, TrkB, GR, Toll-like receptor (TLR) 2/4, and BACE1 [ 142 ]. Computational methods involving target screening are classified based on their principle including pharmacophore screening, shape screening, and reverse docking.…”

Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding

“…The root-mean-square deviation (RMSD) of the protein was analyzed in all systems for the original description of simulation performance and stability, reflecting the general thermodynamic stability of the system (Figure 1d) [37]. The RMSD represents the conformational stability of the protein structure during the course of the simulation, where the larger deviations indicate more flexibility of the protein structure [38]. According to the RMSD plot, all wild and mutant type structures with and without ligand achieved equilibrium after 10 ns and remained stable afterward, which allows an appropriate framework for further analyses [39,40].…”

Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System

“…Phytochemicals and other natural products can directly scavenge oxygen free radicals and enhance the expressions of cellular antioxidant enzymes and molecules (Amato et al, 2019), and thus, protect against OS-mediated cellular injury (Son et al, 2008;Lee et al, 2014;Naoi et al, 2017;Hannan et al, 2020b). These bioactive compounds and their natural sources have been demonstrated to have neuritogenic potentials (Jang et al, 2010;Hannan et al, 2013Hannan et al, , 2014Hannan et al, , 2019 and to aid the reconstruction of synaptic connectivity by regenerating damaged neuronal processes (Moosavi et al, 2015;Venkatesan et al, 2015;Tohda, 2016). In fact, several studies have described a number of natural pharmacological modulators that can co-activate antioxidant defense and neurotrophin signaling-mediated cell survival systems (Gao et al, 2015;Kwon et al, 2015;Zhang et al, 2017;Cui et al, 2018;Fang et al, 2018;Hui et al, 2018), and suggested that these compounds have therapeutic potential for the treatment of OS-mediated brain disorders.…”