Bellerophon: Automated PROTAC Decomposition Tool

---

🚀 Overview

Bellerophon is a computational tool that automatically decomposes heterobifunctional degraders (PROTACs) into their three structural components:
Warhead (target-binding ligand), Linker, and E3 Ligase Ligand.

Accurately splitting PROTACs into their constituent parts is a complex task. Existing resources provide valuable manually curated information but lack automated, flexible parsing.
Bellerophon overcomes this limitation with a structure-based algorithm that identifies and extracts these fragments directly from a PROTAC’s molecular structure.

By standardizing the decomposition process, Bellerophon enables:

• High-throughput annotation and data curation
• Comparison and recombination of validated building blocks
• Structure-driven de novo PROTAC design workflows

---

🔍 How It Works

Bellerophon uses a multi-step, structure-based comparison procedure:

1. The input PROTAC is matched against a curated warhead library.
2. Once the warhead is identified and removed, the remaining structure is compared against the E3 ligase library.
3. The linker is inferred from the remaining molecular fragment.
4. The process is repeated in reverse (starting from the E3 ligand) to ensure consistency.
5. Only decompositions yielding identical linkers in both directions are retained.

To minimize false positives, the algorithm applies multiple structural integrity checks, ensuring the identified components fully reconstruct the original PROTAC (heavy atom count, ring count, and connectivity).

---

⚙️ Implementation

• Language: Python
• Core library: RDKit
• Interface: Streamlit
• Source code and default libraries: Available in this repository
• Web app: 🌐 Bellerophon Streamlit App

---

✨ Features

• Automatic identification of warhead, linker, and E3 ligand
• Consistency validation via heavy-atom and ring-count checks
• Built-in curated libraries (warheads and E3 ligases)
• Option to upload custom .sdf libraries
• Batch processing of multiple PROTACs
• Downloadable results in .csv or .txt format
• Internal error logging and reporting

---

📂 Quick Start

Run Online

👉 Try it instantly on Streamlit:
https://bellerophon-protac-decomposing-tool.streamlit.app/

Run Locally

# Clone the repository
git clone https://github.com/yourusername/bellerophon.git
cd bellerophon

# Install dependencies
pip install -r requirements.txt

# Launch Streamlit app
streamlit run sprotac.py

🧾 Usage

Input Options

1. Paste Mode:
   Directly paste PROTAC names and SMILES strings.

2. File Upload:
   Upload .txt, .csv, or .sdf files containing the columns Name and SMILES.

---

Output

The tool returns a table listing all valid decompositions, including:

• Compound Name
• PROTAC SMILES
• Warhead SMILES
• Linker SMILES
• E3 Ligand SMILES

All results can be downloaded as .csv or .txt files.
A separate file containing any errors encountered during processing is also available.

---

📚 Default Libraries

Curated collections of warheads and E3 ligands are included in the repository.
These were compiled from degraders reported in clinical trials and recent literature.

Users can also upload custom .sdf libraries to tailor the decomposition process to specific datasets or design goals.

---

👩‍🔬 Authors

Developed by the MedChemBeyond Group,
Department of Molecular Biotechnology and Health Sciences,
University of Turin, in collaboration with Alvascience.

📧 Contact: giulia.apprato@unito.it

---

📄 License

This repository is distributed under the MIT License (see LICENSE).
Use is permitted for non-commercial purposes only.

---

🧾 Citation

If you use Bellerophon in your research, please cite:

Bellerophon: A structure-based tool for automatic PROTAC decomposition
Web app: https://bellerophon-protac-decomposing-tool.streamlit.app/

---

🌟 Acknowledgments

Special thanks to contributors from the University of Turin, MedChemBeyond members, Alvascience
for supporting the development of Bellerophon.

---