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A project exploring G-protein-coupled receptors (GPCRs) as therapeutic targets for Long COVID using computational analysis and drug repurposing tools.

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dhanyashri-g/long-covid-therapeutics

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🧬 GPCR-Targeted Therapeutics for Long COVID

A Comprehensive Bioinformatics Study


🧠 Project Overview

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is a chronic condition with lingering symptoms such as fatigue, neurological impairments, and respiratory issues. Current treatment options are limited. This study explores the role of GPCRs, a major class of druggable cell-surface receptors, as potential therapeutic targets. The project integrates multiple bioinformatics approaches to:

  • Identify GPCRs associated with long COVID genes
  • Analyze sequence/function/network relationships
  • Simulate molecular interactions
  • Suggest possible FDA-approved or repurposed drugs

🎯 Research Objectives

  • Functional Mapping: Identify long COVID-related genes with GPCR involvement
  • Network Analysis: Prioritize key GPCR targets using Cytoscape & STRING
  • Docking Simulations: Perform ligand–receptor docking for interaction affinity
  • Drug Repurposing: Highlight potential treatments from known drugs

🧪 Tools & Platforms Used

Tool/Database Purpose
ToppGene / DAVID Functional enrichment, similarity analysis
EMBOSS / BLAST Sequence alignment and comparison
STRING Protein-protein interaction network generation
Cytoscape + CytoHubba Network ranking & hub identification
PPA-Pred Protein-protein affinity docking
PyRx Ligand-receptor docking simulation
Swiss-Model / PDB Structure modeling and retrieval
UCSF Chimera 3D visualization of structures
DrugBank / PubChem Drug annotation and repurposing info

ToppGene DAVID EMBOSS BLAST STRING Cytoscape CytoHubba PPA-Pred PyRx SwissModel PDB Chimera DrugBank PubChem


🔬 Key Findings

This study led to the identification of 21 GPCR-associated genes through functional enrichment, sequence alignment, protein-protein affinity prediction, and docking simulations. These genes were analyzed in connection to long COVID symptoms and their potential as therapeutic targets.

🧠 1. Top Candidate Genes

  • HRAS, KRAS, GNAQ, and GNA11 were consistently identified across multiple analyses.
  • These genes are involved in immune signaling, neurological processes, and cellular communication—core systems disrupted in Long COVID.

💊 2. Repurposed FDA-Approved Drugs Identified

Gene Associated Symptoms Suggested Drugs
GNAQ Venous thrombosis, pulmonary embolism Verteporfin, Selumetinib
GNA11 Ocular pain, alopecia Binimetinib, Cabozantinib, Selumetinib
KRAS Fatigue, GI issues, autoimmunity Panitumumab, Cetuximab, Adagrasib, Sotorasib
PRKACA Memory impairment, mania, alopecia (Limited repurposing data)
  • Additional promising candidates: Naltrexone, Tipifarnib

🔬 3. Docking Results

  • Strong binding affinities (e.g., –9.6 kcal/mol for GNAQ–CAMKK1)
  • RMSD values of 0.0 suggest highly stable receptor-ligand complexes
  • High-confidence docking pairs:
    • GNAQ – CAMKK1
    • PRKACA – PRKACB
    • CAMK2A – CAMK2B

🧬 4. Gene-Symptom Mapping

  • 12 of the 21 genes were mapped to Long COVID symptoms
    • HRAS: Sleep apnea, reflux, alopecia
    • KRAS: Fatigue, edema, abdominal pain
    • PRKAR1A: Irregular menstruation, neuropsychiatric impairment

🌐 5. Network & Enrichment Analysis

  • Cytoscape MCC analysis ranked GNA11 and GNAQ as key hub genes
  • Functional pathways enriched include:
    • GPCR signaling
    • Immune regulation
    • Neurological pathways

🧩 6. Novel Targets

  • Genes like GNA15, GNAT3, PRKCA lack known symptom/drug links—suggesting novel research opportunities

✅ Conclusion & Future Work

This research project offers a comprehensive investigation into the therapeutic potential of G Protein-Coupled Receptors (GPCRs) in managing Long COVID. Through integrated computational approaches, it identified and prioritized 21 GPCR genes as potential therapeutic targets.

🎯 Key Conclusions

  • GPCR genes including HRAS, KRAS, GNAQ, GNA11 were consistently highlighted
  • Repurposed drugs such as Naltrexone, Tipifarnib, Sotorasib, and Cabozantinib showed strong therapeutic relevance
  • The role of GPCRs in immune, neurological, and vascular systems underscores their importance in long COVID

🧪 Challenges and Limitations

  • Reliance on in silico methods; experimental confirmation is pending
  • Default parameter limitations may have excluded borderline results
  • Correlation ≠ causation; findings are hypothesis-generating

🔭 Future Work

  • Experimental validation via in vitro/in vivo studies
  • Biased ligand design for selective GPCR targeting
  • Exploration of autoantibody neutralization strategies
  • Incorporating patient-specific genetic data for personalized therapy
  • Initiating clinical trials for top drug candidates

📸 Visuals & Figures

  • Protein interaction networks
  • Top docking poses and 3D binding visualizations
  • Affinity score charts and heatmaps

All figures are available in the /Figures/ directory.


📘 Reference

Title: Exploring G-Protein Coupled Receptor (GPCR) as Therapeutic Application of Long COVID
Author: Dhanyashri A/P Guruparan
Institution: Management & Science University (MSU), Malaysia
Submitted: 2024

📄 Full Report: [manuscript_LongCovid_Therapeutics.pdf]


📌 How to Use

  1. Browse the folders to explore materials by category (network, docking, simulation).
  2. Open any .pdb or .pdbqt files in UCSF Chimera or PyRx to view 3D structures.
  3. View CSV/Excel files in Docking_PPA-Pred or Docking_Simulation for result summaries.
  4. Use the README to understand the logic behind each experiment.

📜 License

This project is licensed under the MIT License. For academic use only.


💡 Future Work

  • Validation of docking predictions via wet-lab experiments
  • Expansion to other receptor families (e.g., kinases)
  • Multi-drug synergy simulations for combination therapy

| This work is original and solely belongs to the author (Dhanyashri) and MSU. All materials and results are intended for academic and non-commercial research purposes only.

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A project exploring G-protein-coupled receptors (GPCRs) as therapeutic targets for Long COVID using computational analysis and drug repurposing tools.

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