TacoGFN: Target Conditioned GFlowNet for Structure-based Drug Design

Accepted in TMLR (Transaction on Machine Learning Research) and spotlighted in NeurIPS GenBio Workshop 2023 [arxiv].

Official Github for TacoGFN: Target Conditioned GFlowNet for Structure-based Drug Design by Tony Shen, Seonghwan Seo, Grayson Lee, Mohit Pandey, Jason Smith, Artem Cherkasov, Woo Youn Kim and Martin Ester.

We frame structure-based drug design as a Reinforcement Learning task, where the goal is to search the wider chemical space for molecules with desirable properties as opposed to fitting a training data distribution. We propose TacoGFN, a Generative Flow Network conditioned on protein pocket structure, using binding affinity, drug-likeliness and synthesizability measures as our reward.

Empirically, our method outperforms state-of-art methods on the CrossDocked2020 benchmark for every molecular property (Vina score, QED, SA), while improving the generation time by multiple orders of magnitude. TACOGFN achieves −8.82 in median docking score and 52.63% in Novel Hit Rate.

If you have any problems or need help with the code, please add an issue or contact [email protected].

Setup

Before running any scripts, please download the necessary package:

https://figshare.com/s/2738ce20d82463227113

This package includes:

• trained model weights
• pre-computed pharmacophores in lmdb
• saved pocket-graphs in lmdb
• misc files (data splitting, avg vina score, pocket centroid, generated molecules)

Please also setup up Conda Environment and install neccessary dependencies.

conda env create -f environment.yml
conda activate tacogfn
cd src/molvoxel
pip install -e .

Training TacoGFN

If you wish to re-train the model we provide the HPS for 3 model variants presented in our paper:

• TacoGFN: hps/crossdocked_mo_256.json
• TacoGFN (ZINCDock-15M): hps/zinc_mo_256.json
• TacoGFN no pocket conditioning: hps/zinc_mo_256_noph.json

Note: TacoGFN_ranked is the same model as TacoGFN - we just generate 500 instead of 100 molecules at inference time, and rank by predicted docking score. The inference script takes care of that.

python3 src/tacogfn/tasks/pharmaco_frag.py --hps_path "$HPS_PATH"

Generating molecules and computing metrics

If you just wish to generate molecules and evaluate them, we also provide trained models files. The following scripts re-generates molecules and computes metrics on them (Docking needs to be computed seperatly).

bash scripts/generate_and_evaluate.sh

Note if you have re-trained a model, you can specify your model path to generate and evaluate the performance. You can set $NUM_PER_POCKET to 100 for normal runs. If you'd like to run TacoGFN_ranked, please change $NUM_PER_POCKET to 500.

python3 src/tasks/generate_molecules.py \
        --model_path "$MODEL_PATH" \
        --num_per_pocket $NUM_PER_POCKET \
        --comment "${COMMENT}"

python3 src/tasks/evaluate_molecules.py \
    --molecules_path "misc/generated_molecules/1.0_1.0_${NUM_PER_POCKET}_${COMMENT}.json"

Aggregating and displaying metrics

To display the metrics, we provide the generated molecules from our model and baseline models in misc/evaluations. The following scripts computes the metrics used in Table 1 and Table 2:

bash scripts/see_all_results.sh

Note if you've generated molecules from a trained model, please compute docking scores using QVina 2.1 first. Then you could call the following:

python3 src/tasks/aggergate_evals.py --eval_path "$EVAL_FILE"

Citations

@article{
        shen2024tacogfn,
        title={Taco{GFN}: Target-conditioned {GF}lowNet for Structure-based Drug Design},
        author={Tony Shen and Seonghwan Seo and Grayson Lee and Mohit Pandey and Jason R Smith and Artem Cherkasov and Woo Youn Kim and Martin Ester},
        journal={Transactions on Machine Learning Research},
        issn={2835-8856},
        year={2024},
        url={https://openreview.net/forum?id=N8cPv95zOU},
}

This project modifies GFlowNet library for graph and molecular data.