Exploring shared therapeutic targets for Alzheimer's disease and glioblastoma using network pharmacology and protein-protein interaction approach.

in Frontiers in chemistry by Sushma Pradeep, M R Sai Chakith, S R Sindhushree, Pruthvish Reddy, Esther Sushmitha, Madhusudan N Purohit, Divya Suresh, Nanjunda Swamy Shivananju, Ekaterina Silina, Natalia Manturova, Victor Stupin, Shiva Prasad Kollur, Chandan Shivamallu, Raghu Ram Achar

TLDR

  • The study explored the therapeutic potential of luteolin, a phytochemical from Eclipta alba, for Alzheimer's disease and glioblastoma through integrative network pharmacology and molecular docking studies, identifying it as a promising multi-target therapeutic agent.

Abstract

Alzheimer's disease (AD) and glioblastoma (GBM) are complex neurological disorders with distinct pathologies but overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and dysregulated signaling pathways. Despite significant advancements in research, effective therapies targeting both conditions remain elusive. Identifying shared molecular targets and potential therapeutic agents could offer novel treatment strategies for these disorders. The study employs an integrative network pharmacology approach to explore the therapeutic potential of bioactive compounds from, a medicinal herb known for its neuroprotective and anti-inflammatory properties. A systematic methodology was adopted, starting with network pharmacology analysis using STRING and DisGeNET databases, which identified 617 common genes associated with AD and GBM. Among these, key hub genes-TP53, STAT3, AKT1, and IL6-were prioritized using Cytoscape for network visualization and analysis. Molecular docking studies were conducted using PyRx software to assess the binding interactions of 26 phytochemicals from Eclipta alba against the identified target genes. Luteolin exhibited the highest binding affinity to IL6 (-7.8 kcal/mol), forming stable hydrogen bonds and hydrophobic interactions. To further validate this interaction, molecular dynamics simulations (MDS) were performed using GROMACS, confirming the stability of the Luteolin-IL6 complex. Additionally, MM-PBSA binding energy calculations using AmberTools (-145.44 kJ/mol) provided further evidence of a strong and stable interaction. Pharmacokinetic and toxicity evaluations, conducted using SwissADME and pkCSM, highlighted luteolin's favorable drug-like properties, including good bioavailability and low toxicity. These findings suggest that luteolin may serve as a promising multi-target therapeutic agent for AD and GBM by modulating key pathological pathways. The present study provides a strong computational foundation for furtherandvalidation. The results highlight the potential of luteolin in developing dual-target treatment strategies for neurodegenerative and oncological disorders, offering new avenues for therapeutic advancements.

Overview

  • The study employed an integrative network pharmacology approach to explore the therapeutic potential of bioactive compounds from Eclipta alba for Alzheimer's disease (AD) and glioblastoma (GBM).
  • The study aimed to identify shared molecular targets and potential therapeutic agents for AD and GBM, leveraging the herb's neuroprotective and anti-inflammatory properties.
  • The methodology involved network pharmacology analysis, molecular docking studies, and molecular dynamics simulations to assess the binding interactions and pharmacokinetic properties of 26 phytochemicals from Eclipta alba.

Comparative Analysis & Findings

  • The study identified 617 common genes associated with AD and GBM, with four key hub genes (TP53, STAT3, AKT1, and IL6) prioritized for further analysis.
  • Molecular docking studies revealed that luteolin, a phytochemical from Eclipta alba, exhibited the highest binding affinity to IL6 (-7.8 kcal/mol), forming stable hydrogen bonds and hydrophobic interactions.
  • Molecular dynamics simulations and MM-PBSA binding energy calculations confirmed the stability and strength of the Luteolin-IL6 complex, suggesting a strong potential as a multi-target therapeutic agent.

Implications and Future Directions

  • The study highlights the potential of luteolin as a promising therapeutic agent for AD and GBM by modulating key pathological pathways.
  • Future studies should validate the findings through in vitro and in vivo experiments, as well as explore the potential therapeutic benefits of luteolin combination therapy with existing treatments.
  • The study's computational foundation provides a strong basis for further research, offering new avenues for therapeutic advancements in neurodegenerative and oncological disorders.
Read Full Article