# GCDM-SBDD [](https://arxiv.org/abs/2302.04313) [](https://doi.org/10.5281/zenodo.13375913)

Description

This is the official structure-based drug design (SBDD) codebase of the paper

Geometry-Complete Diffusion for 3D Molecule Generation and Optimization, Nature CommsChem

[arXiv] [Nature CommsChem]

Contents

• System requirements
• Installation guide
• Tutorials
• Demo
  • Sample molecules for a given pocket
• Instructions for use
  • Training
  • Reproduce paper results
• Acknowledgements
• License
• Citation

System requirements

OS requirements

This package supports Linux. The package has been tested on the following Linux system: Description: AlmaLinux release 8.9 (Midnight Oncilla)

Python dependencies

This package is developed and tested under Python 3.10.x. The primary Python packages and their versions are as follows. For more details, please refer to the environment.yaml file. python hydra-core=1.3.2 matplotlib-base=3.7.1 numpy=1.24.3 pyg=2.3.0=py310_torch_2.0.0_cu118 python=3.10.11 pytorch=2.0.1=py3.10_cuda11.8_cudnn8.7.0_0 pytorch-scatter=2.1.1=py310_torch_2.0.0_cu118 pytorch-lightning=2.0.2 scikit-learn=1.2.2 torchmetrics=0.11.4

Installation guide

Install mamba (~500 MB: ~1 minute)

bash wget "https://github.com/conda-forge/miniforge/releases/latest/download/Mambaforge-$(uname)-$(uname -m).sh" bash Mambaforge-$(uname)-$(uname -m).sh # accept all terms and install to the default location rm Mambaforge-$(uname)-$(uname -m).sh # (optionally) remove installer after using it source ~/.bashrc # alternatively, one can restart their shell session to achieve the same result

Install dependencies (~15 GB: ~10 minutes)

```bash

clone project

git clone https://github.com/BioinfoMachineLearning/GCDM-SBDD cd GCDM-SBDD

create conda environment

mamba env create -f environment.yaml conda activate GCDM-SBDD # note: one still needs to use conda to (de)activate environments

install local project as package

pip3 install -e . ```

Download checkpoints (~500 MB extracted: ~2 minutes)

Note: Make sure to be located in the project's root directory beforehand (e.g., ~/GCDM-SBDD/) ```bash

fetch and extract model checkpoints directory

wget https://zenodo.org/record/13375913/files/GCDMSBDDCheckpoints.tar.gz tar -xzf GCDMSBDDCheckpoints.tar.gz rm GCDMSBDDCheckpoints.tar.gz ```

NOTE: Trained EGNN baseline checkpoint files are also included in GCDM_SBDD_Checkpoints.tar.gz.

QuickVina 2

For docking, download QuickVina 2 and copy it to your Conda environment's binary (bin) directory: bash wget https://github.com/QVina/qvina/raw/master/bin/qvina2.1 chmod +x qvina2.1 mv qvina2.1 $HOME/mambaforge/envs/GCDM-SBDD/bin

We need MGLTools for preparing the receptor for docking (pdb -> pdbqt) but it can mess up your Mamba environment, so I recommend making a new one: bash mamba create -n mgltools -c bioconda mgltools

Binding MOAD

Data preparation

Download the dataset ```bash wget https://zenodo.org/record/13375913/files/everyparta.zip wget https://zenodo.org/record/13375913/files/everypartb.zip wget https://zenodo.org/record/13375913/files/every.csv

unzip everyparta.zip unzip everypartb.zip Process the raw data using bash python processbindingmoad.py <bindingmoaddir> or, to suppress warnings, bash python -W ignore processbindingmoad.py <bindingmoaddir> ```

CrossDocked Benchmark

Data preparation

Download and extract the dataset as described by the authors of Pocket2Mol: https://github.com/pengxingang/Pocket2Mol/tree/main/data

Process the raw data using bash python process_crossdock.py <crossdocked_dir> --no_H

Finetuning Set

Data preparation

Download your desired finetuning dataset of protein-ligand complexes, each stored in a single PDB file (e.g., 1a4z_LIG:A:403.pdb), to data/finetuning_set, and then run bash python process_finetuning_set.py <finetuning_set_dir> or, to suppress warnings, bash python -W ignore process_finetuning_set.py <finetuning_set_dir>

Tutorials

We provide a two-part tutorial series of Jupyter notebooks to provide users with a real-world example of how to use GCDM-SBDD for pocket-based molecule generation and filtering, as outlined below.

1. Generating molecules in target protein pockets
2. Filtering generated molecules using PoseBusters

Demo

Sample molecules for a given pocket

To sample small molecules for a given pocket with a trained model use the following command: bash python generate_ligands.py <checkpoint>.ckpt --pdbfile <pdb_file>.pdb --outdir <output_dir> --resi_list <list_of_pocket_residue_ids> For example: bash python generate_ligands.py last.ckpt --pdbfile 1abc.pdb --outdir results/ --resi_list A:1 A:2 A:3 A:4 A:5 A:6 A:7 Alternatively, the binding pocket can also be specified based on a reference ligand in the same PDB file: bash python generate_ligands.py <checkpoint>.ckpt --pdbfile <pdb_file>.pdb --outdir <output_dir> --ref_ligand <chain>:<resi>

Optional flags: | Flag | Description | |------|-------------| | --n_samples | Number of sampled molecules | | --all_frags | Keep all disconnected fragments | | --sanitize | Sanitize molecules (invalid molecules will be removed if this flag is present) | | --relax | Relax generated structure in force field | | --resamplings | Inpainting parameter (doesn't apply if conditional model is used) | | --jump_length | Inpainting parameter (doesn't apply if conditional model is used) |

Instructions for use

Training

Starting a new training run: bash python -u train.py config=<config>.yml

Resuming a previous run: bash python -u train.py config=<config>.yml resume=<checkpoint>.ckpt

Reproduce paper results

test.py can be used to sample molecules for the entire testing set: bash python test.py <checkpoint>.ckpt --test_dir <bindingmoad_dir>/processed_noH/test/ --outdir <output_dir> --fix_n_nodes Using the optional --fix_n_nodes flag lets the model produce ligands with the same number of nodes as the original molecule. Other optional flags are identical to generate_ligands.py.

Compute sample metrics

For assessing basic molecular properties create an instance of the MoleculeProperties class and run its evaluate method: python from analysis.metrics import MoleculeProperties mol_metrics = MoleculeProperties() all_qed, all_sa, all_logp, all_lipinski, per_pocket_diversity = \ mol_metrics.evaluate(pocket_mols) evaluate() expects a list of lists where the inner list contains all RDKit molecules generated for one pocket.

For computing docking scores, run QuickVina as described below.

Run QuickVina2

First, convert all protein PDB files to PDBQT files using MGLTools bash conda activate mgltools cd analysis python2 docking_py27.py <bindingmoad_dir>/processed_noH/test/ <output_dir> bindingmoad cd .. conda deactivate Then, compute QuickVina scores: bash conda activate GCDM-SBDD python3 analysis/docking.py --pdbqt_dir <docking_py27_outdir> --sdf_dir <test_outdir> --out_dir <qvina_outdir> --write_csv --write_dict --dataset moad

NOTE: One can reference analysis/inference_analysis.py and analysis/molecule_analysis.py to analyze the generated molecules.

Docker

To build this project in a Docker container, you can use the following commands:

```bash

Build the image

docker build -t gcdm-sbdd .

Run the container (with GPUs and mounting the current directory)

docker run -it --gpus all -v .:/mnt --name gcdm-sbdd gcdm-sbdd ```

This Docker image is also available on Docker Hub at cford38/gcdm-sbdd, which can be run with the following command:

```bash

docker pull cford38/gcdm-sbdd

docker run -it --gpus all -v .:/mnt --name gcdm-sbdd cford38/gcdm-sbdd `` (Note: This image includes the checkpoints in the main working directory/software/GCDM-SBDD/checkpoints/`.)

Acknowledgements

GCDM-SBDD builds upon the source code and data from the following projects:

• Bio-Diffusion
• DiffSBDD
• GCPNet
• PoseBusters

We thank all their contributors and maintainers!

License

This project is covered under the MIT License.

Citation

If you use the code or data associated with this package or otherwise find this work useful, please cite:

bibtex @article{morehead2024geometry, title={Geometry-complete diffusion for 3D molecule generation and optimization}, author={Morehead, Alex and Cheng, Jianlin}, journal={Communications Chemistry}, volume={7}, number={1}, pages={150}, year={2024}, publisher={Nature Publishing Group UK London} }