DrugRepurposing_MMP2_Docking-MD-Simulation

Practice

(Research Project Practice and troubleshooting exercise)

This repository contains a computational practice project on drug repurposing of cephalosporins against MMP-2 (Matrix Metalloproteinase-2), a key target in tumor progression and metastasis.

It documents the workflow — from protein preparation to docking and normal mode analysis — along with results and visualizations.

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🔹 Workflow Overview

1. Protein Selection & Preparation

• Target: MMP-2
  • UniProt ID: P08253
  • PDB ID: 7XJO (catalytic domain, 2.0 Å resolution)
• Cleaned in Discovery Studio (removed water, ligands, ions, Chain B → kept single Chain A).
• Refined with GalaxyRefine (Model 5 chosen).
• Validation:
  • ERRAT score improved from 78 → 95
  • PROCHECK Ramachandran: 95.6% residues in favored regions

2. Protein Analysis

• ProtParam: Stable (Instability Index = 27.46), acidic pI (5.26), soluble (GRAVY = –0.446).
• PSIPRED: Balanced α-helices and β-sheets, well-defined structure.

3. Ligand Selection & Preparation

• Cephalosporins retrieved from PubChem:
  Cefoperazone, Ceftizoxime, Ceftazidime, Cefixime, Cefditoren, Ceftibuten, Cefpodoxime, Cefotaxime.
• ADME analysis via SwissADME (GI absorption, MW, TPSA, Lipinski).
• Converted: SDF → PDB → PDBQT (OpenBabel + AutoDockTools).

4. Molecular Docking (AutoDock Vina)

• Binding pocket defined using co-crystallized inhibitor from 7XJO.
• Docking performed (single + batch mode).
• Docking Scores (kcal/mol):
  • Cefoperazone: –7.061 ✅ (best)
  • Ceftizoxime: –6.996
  • Ceftazidime: –6.691
  • Others ranged –5.8 to –6.5

👉 See docking_scores.csv file for full results.

5. Post-docking Analysis

• Complex formed only with Cefoperazone (top hit).
• PLIP Analysis:
  • H-bonds → LEU83, ALA84, ALA86, ALA88
  • Salt bridges → HIS121, HIS125, HIS131
  • π–π stacking → PHE87
• Visualization: Complex generated in PyMOL.

6. Molecular Dynamics Simulation (iMODS)

• Normal Mode Analysis (NMA) confirmed structural stability of the MMP-2–Cefoperazone complex.

Plots exported from iMODS:

• deformability.png → deformability of residues
• bfactor.png → normalized B-factor plot
• eigenvalue.png → eigenvalue (stiffness of motion)
• covariance.png → covariance map (correlated/anticorrelated motions)
• elastic_network.png → elastic network model

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📂 Repository Structure

MMP2_DrugRepurposing/
│
├── README.md
├── Docking_Results.docx # Full detailed report
│
├── data/
│   ├── protein/ # Protein files (raw, cleaned, refined, validation)
│   └── ligands/ # Ligands (SDF, PDB, PDBQT, ADME reports)
│
├── docking/
│   ├── config_single.txt # config for single docking
│   ├── config_batch.txt # config for batch docking
│   ├── commands.txt # commands used
│   ├── docking_scores.csv # docking results
│   └── Results/ # Vina outputs
│       ├── out_files/ # .pdbqt
│       ├── logs/ # .txt
│       └── split_poses/ # vina_split outputs
│
└── analysis/
    ├── plip/ # Protein–ligand interaction analysis
    │   ├── MMP2_Cefoperazone_complex.pdb
    │   ├── PLIP_report.xml
    │   └── 2D_Diagram_PLIP.png
    │
    └── imods/ # Molecular dynamics (iMODS)
        ├── index.html
        ├── index2.html
        ├── deformability.png
        ├── bfactor.png
        ├── eigenvalue.png
        ├── covariance.png
        ├── elastic_network.png
        └── model.pdb

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🔹 Key Takeaways

• Cefoperazone emerged as the strongest binder to MMP-2 (–7.061 kcal/mol).
• Stable hydrogen bonds, salt bridges, and π–π stacking confirmed via PLIP.
• iMODS simulation validated overall structural stability.

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🛠 Tools & Servers Used

• Docking & Prep: AutoDock Vina, MGLTools (ADT), Discovery Studio, PyMOL, OpenBabel

• Protein analysis: ProtParam, PSIPRED, GalaxyRefine, ERRAT, PROCHECK

• Ligand analysis: SwissADME, PubChem

• Interaction analysis: PLIP, PyMOL

• MD simulation: iMODS

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📚 Related Research Publication

This research practice involves drug repurposing analysis on MMP-2, using a different protein ID than the one used in our published research.
The workflow here is a practice and troubleshooting exercise, while the publication presents the formal, peer-reviewed analysis with deeper computational validation.

Research Article:
📄 “In Silico Discovery of Cefoperazone as a Novel MMP-2 Inhibitor for Ovarian Cancer Therapy”
Published in Scientific Inquiry and Review

🔗 Full Text:
https://journals.umt.edu.pk/index.php/SIR/article/view/7532

Summary of the Publication:

• Evaluated eight cephalosporins against MMP-2.
• Cefoperazone showed the strongest binding (ΔG = –8.1 kcal/mol).
• 100-ns MD simulations validated complex stability.
• Highlights the potential of in-silico drug repurposing in early-stage oncology research.

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🙏 Feedback

Your reads, critical feedback, and citations are greatly appreciated and help amplify the impact of this work.

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⚖️ License

This repository is shared under the MIT License — feel free to use and adapt with proper attribution.