Title:Exploring the Potential of Dolutegravir in Alzheimer's Disease Treatment: Insights from Network Pharmacology and In Silico Docking Studies
Volume: 26
Issue: 1
Author(s): Karishma M. Rathi*, Nikhil S. Sakle, Vaishali R. Undale, Ravindra D. Wavhale, Ritesh P. Bhole and Pawan N. Karwa
Affiliation:
- Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Sant Tukaram Nagar, Pimpri, Pune, 411018, India
Keywords:
Alzhimers disease, dolutegravir, drug repurposing, network pharmacology, KEGG pathway, molecular docking.
Abstract:
Background: The search for effective treatments for neurodegenerative diseases,
particularly Alzheimer's disease, has been fraught with challenges. Alzheimer's disease accounts
for 60-80% of dementia cases globally, affecting approximately about 50 million people.
Currently, drug repurposing has emerged as a promising strategy in new drug development, attracting
significant attention from regulatory agencies, such as the US FDA.
Aims: This study aimed to investigate the potential therapeutic role of dolutegravir in Alzheimer's
disease (AD) treatment using a novel network pharmacology approach. Specifically, it
explored the interaction of dolutegravir with key molecular targets involved in AD pathology,
predicted its effects on relevant biological pathways, and evaluated its viability as a new therapeutic
candidate.
Objective: This study employed a network pharmacology framework to evaluate dolutegravir,
an antiretroviral drug, as a potential treatment for Alzheimer's disease, shedding light on its
possible therapeutic mechanisms.
Methods: A network pharmacology approach was used to predict the drug targets of dolutegravir.
Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes
(KEGG) pathway analyses were performed to identify interacting pathways. Additionally, protein-
protein interaction (PPI) network analysis was conducted to assess key interactions and
molecular docking studies were performed to evaluate the binding affinity of dolutegravir to the
predicted targets.
Results: PPI network analysis revealed that dolutegravir interacted with several key targets, including
BRAF, mTOR, MAPK1, MAPK3, NOS1, BACE1, CAPN1, CASP3, CASP7, CASP8,
CHUK, IKBKB, PIK3CA, and PIK3CD. KEGG pathway analysis suggested that dolutegravir
could influence amyloid-beta formation, amyloid precursor protein metabolism, and the cellular
response to amyloid-beta. Molecular docking results showed the highest binding affinity of dolutegravir
for PI3KCD (-8.5 kcal/mol) and MTOR (-8.7 kcal/mol).
Conclusion: The findings indicated that dolutegravir holds significant potential in modulating
key pathways involved in Alzheimer's disease pathogenesis. These results provide a strong
foundation for further investigations into the therapeutic efficacy and safety of dolutegravir in
the treatment of Alzheimer's disease. The use of drug repurposing strategies, leveraging Dolutegravir's
established pharmacological profile, offers a promising route for accelerated therapeutic
development in AD.
