MolDiff: Addressing the Atom-Bond Inconsistency Problem in 3D Molecule Diffusion Generation (ICML 2023)

This is A Tailored Diffusion Framework for Generating 3D Drug-Like Molecules, with sampling success rate of >99%, almost threefold increase compared to the previous diffusion model.

This can serve as a better backbone for other applications of 3D molecule diffusion models such as pocket-based generation and linker generation.

More information can be found in our paper.

Installation

Dependency

The codes have been tested in the following environment:

Package	Version
Python	3.8.13
PyTorch	1.10.1
CUDA	11.3.1
PyTorch Geometric	2.0.4
RDKit	2022.03.2

Install via conda yaml file (cuda 11.3)

conda env create -f env.yaml
conda activate MolDiff

Install manually

conda create -n MolDiff python=3.8 # optinal, create a new environment
conda activate MolDiff

# Install PyTorch (for cuda 11.3)
conda install pytorch==1.10.1 cudatoolkit=11.3 -c pytorch -c conda-forge
conda install pyg -c pyg

# Install other tools
conda install -c conda-forge rdkit
conda install pyyaml easydict python-lmdb -c conda-forge

# Install tensorboard only for training
conda install tensorboard -c conda-forge

Dataset

Processed data

You can download the processed data geom_drug.tar.gz (~2GB) from here and unzip them (tar -zxvf) in the data folder as:

data
├── geom_drug
│   ├── mol_summary.csv
│   ├── split_by_molid.pt
│   ├── processed.lmdb
│   └── processed_molid2idx.pt

From sdf files

If you want to process the data from the sdf files, you have to further download the sdf.tar.gz (~4GB) from here. Unzip it (~28GB after unzipping) in the data/geom_drug folder and remove the processed.lmdb and processed_molid2idx.pt:

data
├── geom_drug
│   ├── mol_summary.csv
│   ├── split_by_molid.pt
│   └── sdf
│       ├── 0.sdf
│       ├── 1.sdf
│       ├── ...

Then by running any sampling, training or evaluation script, the data will be processed automatically.

Sample

We provide the sampling config file sample_MolDiff.yml in configs/sample folder. We also provide a simplified version of MolDiff sample_MolDiff_simple.yml that does not use the bond guidance for sampling and uses the model trained without the new bond noise schedule proposed in the paper.

To sample molecules using pretrained models, please first download the pretrained model weights from here and put them in the ./ckpt folder. There are three model weight files:

• MolDiff.pt: the pretrained complete MolDiff model.
• MolDiff_simple.pt: the pretrained simplified MolDiff model that was trained without using the new bond noise schedule.
• bond_predictor.pt: the pretrained bond predictor that is used for bond guidance during sampling.

After preparing the pretrained weights (either the downloaded files or trained by yourself) and setting the correct model weight paths in the config file, you can run the following command to sample molecules:

python scripts/sample_drug3d.py --outdir <output_directory> --config <path_to_config_file> --device <device_id> --batch_size <batch_size>

The parameters are:

• outdir: the root directory to save the sampled molecules.
• config: the path to the config file.
• device: the device to run the sampling.
• batch_size: the batch size for sampling. If set to 0 (default), it will use the batch size specified in the config file.

An example command is:

python scripts/sample_drug3d.py --outdir ./outputs --config ./configs/sample/sample_MolDiff.yml

After sampling, there will be two directories in the outdir folder that contains the meta data and the sdf files of the sampling, respectively.

Evaluate

To evaluate the generated molecules, run the following command:

python scripts/evaluate_all.py --result_root <result_root> --exp_name <exp_name> --from_where generated

The parameters are:

• result_root: the parent directory of the directory of the sampled molecules (i.e, the same as the outdir parameter when running sample_drug3d.py).
• exp_name: the name (or prefix) of the directory of the molecules (excluding the suffix _SDF).
• from_where: be one of generated of dataset.

An example command to calculate metrics for the sampled molecules is:

python scripts/evaluate_all.py --result_root ./outputs --exp_name sample_MolDiff_20230101_000000 --from_where generated

You also need to calculate some metrics for the test dataset to calculate the Jensen-Shannon divergence (JSD) between the generated molecules and the test dataset. To do so, run the following command:

python scripts/evaluate_all.py --exp_name test --from_where dataset

Then you can use the interactive notebook script/analyze_generated.ipynb to analyze all the metrics defined in the paper. But make sure to set the directory of the sampled molecules and the test dataset correctly in the notebook.

Train

We also provide two versions of training config files: the complete MolDiff train_MolDiff.yml and the simplified one train_MolDiff_simple.yml (not use the new bond noise schedule). To train the model from scratch, run the following command:

python scripts/train_drug3d.py --config <path_to_config_file> --device <device_id> --logdir <log_directory>

For example, to train the complete MolDiff model, run:

python scripts/train_drug3d.py --config ./configs/train/train_MolDiff.yml --device cuda:0 --logdir ./logs

To use the bond predictor for guidance during sampling, you also need to train a bond predictor:

python scripts/train_bond.py --config ./configs/train/train_bondpred.yml --device cuda:1 --logdir ./logs

Citation

@InProceedings{pmlr-v202-peng23b,
  title =   {{M}ol{D}iff: Addressing the Atom-Bond Inconsistency Problem in 3{D} Molecule Diffusion Generation},
  author =       {Peng, Xingang and Guan, Jiaqi and Liu, Qiang and Ma, Jianzhu},
  booktitle =   {Proceedings of the 40th International Conference on Machine Learning},
  pages =   {27611--27629},
  year =   {2023},
  editor =   {Krause, Andreas and Brunskill, Emma and Cho, Kyunghyun and Engelhardt, Barbara and Sabato, Sivan and Scarlett, Jonathan},
  volume =   {202},
  series =   {Proceedings of Machine Learning Research},
  month =   {23--29 Jul},
  publisher =    {PMLR},
  pdf =   {https://proceedings.mlr.press/v202/peng23b/peng23b.pdf},
  url =   {https://proceedings.mlr.press/v202/peng23b.html},
}

Contact

If you have any question, feel free to contact me at [email protected]