Computational Identification of Natural Polyphenols Modulating BDNF–TrkB Signaling in Neurodegeneration

Natural Polyphenols Modulating BDNF–TrkB Signaling in Neurodegeneration

Abstract

The neuronal survival and synaptic plasticity require brain-derived neurotrophic factor (BDNF) to stimulate the tropomyosin receptor kinase B (TrkB). BDNF-TRKB activity, which is lower than normal, is involved in the pathogenesis of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Objectives: To screen computationally natural polyphenolic and alkaloid compounds to discover candidates with the ability to modulate BDNF–TrkB signaling by direct receptor activity and indirect neuroprotective effects. Methods: Molecular docking of the TrkB-D5 domain was conducted in AutoDock Vina, and then the molecular dynamics simulations were conducted to determine binding stability. Physicochemical determinants of binding affinity were identified with the help of quantitative structure-activity relationship (QSAR) models (n=30 compounds). In predicting ADMET properties and blood-brain barrier (BBB) permeability, pkCSM was used, and network pharmacology analysis was used to predict possible multi-target engagement. Results: Catechin had the highest proposed affinity of binding TrkB (ΔG = -8.5 + 0.2 kcal/mol) with constant interactions in molecular dynamics simulations. Thymoquinone demonstrated poor direct binding to TrkB but had good predicted BBB permeability and multi-target interactions with respect to neuroinflammation and oxidative stress. Lipophilicity and decreased polar surface area were determined by QSAR analysis as important factors in the binding affinity. Conclusions: This computational analysis provides catechin as a direct TrkB-interacting compound of interest and thymoquinone as an indirect modulator of the BDNF-related pathways. These results are hypothesis-generating and give a reason as to why they are to be validated experimentally in the future.