RxnFlow: Generative Flows on Synthetic Pathway for Drug Design

Official implementation of Generative Flows on Synthetic Pathway for Drug Design by Seonghwan Seo, Minsu Kim, Tony Shen, Martin Ester, Jinkyu Park, Sungsoo Ahn, and Woo Youn Kim. [arXiv]

RxnFlow are a synthesis-oriented generative framework that aims to discover diverse drug candidates through GFlowNet objective and a large action space.

• RxnFlow can operate on large synthetic action spaces comprising 1.2M building blocks and 117 reaction templates without compute overhead
• RxnFlow can explore broader chemical space within less reaction steps, resulting in higher diversity, higher potency, and lower synthetic complexity of generated molecules.
• RxnFlow can generate molecules with expanded or modified building block libaries without retraining.

This project is based on gflownet, and src/gflownet/ is a clone of recursionpharma/gflownet@v0.2.0. Since we have updated the gflownet version and performed modularization after submission, we do not guarantee that current version will reproduce the same results as the paper. You can access the reproducing codes and scripts from tag: paper-archive.

This repository was developed for research. The code for real-world drug discovery will be released later.

Setup

Install

# python: 3.10
conda install openbabel # For PharmacoNet
pip install -e . --find-links https://data.pyg.org/whl/torch-2.3.1+cu121.html

# For UniDock
conda install openbabel unidock
pip install -e '.[unidock]' --find-links https://data.pyg.org/whl/torch-2.3.1+cu121.html

Data

To construct the synthetic action space, RxnFlow requires the reaction template set and the building block library. We provide two reaction template set:

• We provide the reaction template set data/templates/real.txt from Enamine REAL synthesis protocol (Gao et al.).
• The reaction template used in this paper contains 13 uni-molecular reactions and 58 bi-molecular reactions, which is constructed by Cretu et al. The template set is available under data/templates/hb_edited.txt.

The Enamine building block library is available upon request at https://enamine.net/building-blocks/building-blocks-catalog. We used the "Comprehensive Catalog" released at 2024.06.10.

• Use Comprehensive Catalog

  cd data
  # case1: single-step
  python scripts/a_sdf_to_env.py -b <CATALOG_SDF> -d envs/enamine_all --cpu <CPU>
  
  # case2: two-step
  python scripts/b1_sdf_to_smi.py -b <CATALOG_SDF> -o building_blocks/blocks.smi --cpu <CPU>
  python scripts/b2_smi_to_env.py -b building_blocks/blocks.smi -d envs/enamine_all --cpu <CPU> --skip_sanitize
  python scripts/b2_smi_to_env.py -b building_blocks/blocks.smi -d envs/real -t tesmplates/real.txt --cpu <CPU> --skip_sanitize

• Use custom SMILES file (.smi)

  python scripts/b2_smi_to_env.py -b <SMILES-FILE> -d ./envs/<ENV> -t ./templates/<RXN> --cpu <CPU>

Experiments

Docking optimization with GPU-accelerated UniDock

You can optimize the docking score with GPU-accelerated UniDock.

python script/opt_unidock.py -h
python script/opt_unidock.py \
  -p <Protein PDB path> \
  -c <Center X> <Center Y> <Center Z> \
  -l <Reference ligand, required if center is empty. > \
  -s <Size X> <Size Y> <Size Z> \
  -o <Output directory> \
  -n <Num Oracles (default: 1000)> \
  --filter <drugfilter; choice=(lipinski, veber, null); default: lipinski> \
  --batch_size <Num generations per oracle; default: 64> \
  --env_dir <Environment directory> \
  --subsample_ratio <Subsample ratio; memory-variance trade-off; default: 0.01>

You can also perform multi-objective optimization (Multi-objective GFlowNet) for docking score and QED.

python script/opt_unidock_moo.py -h
python script/opt_unidock_moo.py \
  -p <Protein PDB path> \
  -c <Center X> <Center Y> <Center Z> \
  -l <Reference ligand, required if center is empty. > \
  -s <Size X> <Size Y> <Size Z> \
  -o <Output directory> \
  -n <Num Oracles (default: 1000)> \
  --batch_size <Num generations per oracle; default: 64> \
  --env_dir <Environment directory> \
  --subsample_ratio <Subsample ratio; memory-variance trade-off; default: 0.01>

Example (KRAS G12C mutation)

• Use center coordinates

  python script/opt_unidock.py -p ./data/examples/6oim_protein.pdb -c 1.872 -8.260 -1.361 -o ./log/kras --filter veber
  python script/opt_unidock_moo.py -p ./data/examples/6oim_protein.pdb -c 1.872 -8.260 -1.361 -o ./log/kras --filter veber

• Use center of the reference ligand

  python script/opt_unidock.py -p ./data/examples/6oim_protein.pdb -l ./data/examples/6oim_ligand.pdb -o ./log/kras
  python script/opt_unidock_moo.py -p ./data/examples/6oim_protein.pdb -l ./data/examples/6oim_ligand.pdb -o ./log/kras

Zero-shot sampling with Pharmacophore-based QuickVina Proxy

Not Implemented yet

Sample high-affinity molecules. The QuickVina docking score is estimated by Proxy Model [github].

python script/sampling_zeroshot.py -h
python script/sampling_zeroshot.py \
  -p <Protein PDB path> \
  -c <Center X> <Center Y> <Center Z> \
  -l <Reference ligand, required if center is empty. > \
  -o <Output path: `smi|csv`> \
  -n <Num samples (default: 100)> \
  --env_dir <Environment directory> \
  --model_path <Checkpoint path; default: None (auto-downloaded)> \
  --subsample_ratio <Subsample ratio; memory-variance trade-off; default: 0.01> \
  --cuda

Example (KRAS G12C mutation)

• csv format: save molecules with their rewards (GPU is recommended)

  python script/sampling_zeroshot.py -o out.csv -p ./data/examples/6oim_protein.pdb -l ./data/examples/6oim_ligand.pdb --cuda

• smi format: save molecules only (CPU: 0.06s/mol, GPU: 0.04s/mol)

  python script/sampling_zeroshot.py -o out.smi -p ./data/examples/6oim_protein.pdb -c 1.872 -8.260 -1.361

Custom optimization

If you want to train RxnFlow with your custom reward function, you can use the base classes from rxnflow.base. The reward should be Non-negative.

• Example (QED)

  import torch
  from rdkit.Chem import Mol as RDMol, QED
  from gflownet import ObjectProperties
  from rxnflow.base import RxnFlowTrainer, RxnFlowSampler, BaseTask
  
  class QEDTask(BaseTask):
      def compute_obj_properties(self, objs: list[RDMol]) -> tuple[ObjectProperties, torch.Tensor]:
          fr = torch.tensor([QED.qed(mol) for mol in mols], dtype=torch.float).reshape(-1, 1)
          is_valid_t = torch.ones((len(mols),), dtype=torch.bool)
          return ObjectProperties(fr), is_valid_t
  
  class QEDTrainer(RxnFlowTrainer):  # For online training
      def setup_task(self):
          self.task: QEDTask = QEDTask(cfg=self.cfg, wrap_model=self._wrap_for_mp)
  
  class QEDSampler(RxnFlowSampler):  # Sampling with pre-trained GFlowNet
      def setup_task(self):
          self.task: QEDTask = QEDTask(cfg=self.cfg, wrap_model=self._wrap_for_mp)

Reproducing experimental results

Current version do not provide the reproducing code. Please switch to tag: paper-archive.

Citation

If you use our code in your research, we kindly ask that you consider citing our work in papers:

@article{seo2024generative,
  title={Generative Flows on Synthetic Pathway for Drug Design},
  author={Seo, Seonghwan and Kim, Minsu and Shen, Tony and Ester, Martin and Park, Jinkyoo and Ahn, Sungsoo and Kim, Woo Youn},
  journal={arXiv preprint arXiv:2410.04542},
  year={2024}
}
@article{shen2024tacogfn,
  title={TacoGFN: Target Conditioned GFlowNet for Structure-Based Drug Design},
  author={Shen, Tony and Seo, Seonghwan and Lee, Grayson and Pandey, Mohit and Smith, Jason R and Cherkasov, Artem and Kim, Woo Youn and Ester, Martin},
  journal={arXiv preprint arXiv:2310.03223},
  year={2024},
  note={Published in Transactions on Machine Learning Research(TMLR)}
}
@article{seo2023molecular,
  title={Molecular generative model via retrosynthetically prepared chemical building block assembly},
  author={Seo, Seonghwan and Lim, Jaechang and Kim, Woo Youn},
  journal={Advanced Science},
  volume={10},
  number={8},
  pages={2206674},
  year={2023},
  publisher={Wiley Online Library}
}

Related Works

• GFlowNet (github: recursionpharma/gflownet)
• TacoGFN [github: tsa87/TacoGFN-SBDD]
• PharmacoNet [github: SeonghwanSeo/PharmacoNet]
• UniDock [github: dptech-corp/Uni-Dock]