Imane Kandil

Morocco

5-Hydroxy-7, 4 -dimethoxyflavone In silico Exploration as a New TrkB Receptor agonist: A Comparative Study with apigenin in depression therapy.

Imane Kandil1 and Ahmed Talbaoui1

1Laboratory of Biological Human Pathology, Faculty of Science, Mohammed V University, Rabat-Morocco.

Abstract

Background

This study investigates the structural optimization of natural flavonoids for improved TrkB receptor targeting, a key therapeutic strategy for neurodegenerative disorders.

Methods

Through comparative molecular docking analysis, structural analysis, and ADME profiling.

Results

We demonstrate that 5-Hydroxy-7,4′-dimethoxyflavone exhibits superior binding affinity (-8.5 kcal/mol) compared to its parent compound apigenin (-7.1 kcal/mol) for the BDNF-binding site of TrkB. The strategic methylation at positions 7 and 4′ enhances hydrophobic interactions with ILE-110 and VAL-119 while maintaining crucial hydrogen bonds with ASP-112 and TYR-115. Structural analysis reveals that the methoxy groups improve binding pocket complementarity, increasing contact surface by 23% versus apigenin. ADME profiling confirms maintained blood-brain barrier permeability (Log P =2.7) with improved metabolic stability.

Conclusions

This systematic comparison provides valuable structure-activity relationship insights for developing optimized natural product-based neurotherapeutics, positioning 5-Hydroxy-7,4′-dimethoxyflavone as a promising lead compound worthy of experimental validation.