Investigating the Potential of Natural Small Molecules as BDNF Mimics for Neurodegenerative Disease Treatment: A Molecular Docking Study with TrkB Receptor

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by the progressive degeneration of neurons and dysfunction of the nervous system. A major contributing factor in these diseases is the reduced level and activity of Brain-Derived Neurotrophic Factor (BDNF), a protein essential for neuronal survival, growth, and function. BDNF exerts its effects by binding to its primary receptor, TrkB, which triggers downstream signaling pathways that protect neurons from degeneration and enhance neuroplasticity. In neurodegenerative diseases, the diminished activity of BDNF contributes to neuronal apoptosis, impaired synaptic plasticity, and reduced cognitive function, making it a promising therapeutic target. Given the critical role of BDNF in maintaining neuronal health, mimicking its neurotrophic effects through small molecules presents a novel and potentially effective therapeutic strategy. The primary objective of this study is to explore the potential of several natural small molecules as BDNF mimics by assessing their ability to activate the TrkB receptor. The molecules selected for investigation—Quercetin, Berberine, Baicalein, Oleuropein, Apigenin, Curcumin, and Resveratrol—are known for their antioxidant, anti-inflammatory, and neuroprotective properties. They have also demonstrated therapeutic promise in various in vitro and in vivo models of neurodegeneration. To simulate interactions between these compounds and the TrkB receptor, the ۳D structure of the TrkB receptor (PDB ID: ۱HCF) was retrieved from the Protein Data Bank, and the structures of the small molecules were obtained from the PubChem database. These compounds—Quercetin (CID: ۵۲۸۰۳۴۳), Berberine (CID: ۲۳۵۳), Baicalein (CID: ۵۲۸۱۶۰۵), Oleuropein (CID: ۵۲۸۱۵۴۴), Apigenin (CID: ۵۲۸۰۴۴۳), Curcumin (CID: ۹۶۹۵۱۶), and Resveratrol (CID: ۴۴۵۱۵۴)—were optimized using VEGA ZZ software. The TrkB receptor was also prepared for docking using AutoDockTools (ADT, version ۱.۵.۷). Molecular docking simulations were conducted with AutoDock Vina (version ۱.۱.۲). The simulations allowed for the evaluation of docking scores, binding modes, and the stability of ligand-TrkB complexes. The results revealed that Quercetin, Berberine, and Baicalein exhibited the strongest binding affinities for the TrkB receptor, with docking scores of -۶.۵ kcal/mol. These findings indicate that these natural compounds may effectively mimic BDNF’s action and activate TrkB receptor signaling pathways, providing neuroprotective effects similar to those of BDNF. In conclusion, this study highlights the potential of natural small molecules as promising candidates for therapeutic development aimed at mimicking BDNF and providing neuroprotection in neurodegenerative diseases. The findings from this in silico study provide a strong foundation for further in vitro and in vivo studies to validate these results.

کلیدواژه ها:

BDNF Mimetics ، small molecule ، TrkB ، molecular docking