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POLYpharmacology Generative Optimization Network (POLYGON) a VAE for de novo polypharmacology.

This repository contains the POLYGON framework, a de novo molecular generator for polypharmacology. Akin to de novo portait generation, POLYGON attempts to optimize the chemical space for multiple protein target domains.

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The codebase is primarily adapted from two excellent de novo molecular design frameworks:

GuacaMol for reward based reinforcement learning: https://github.com/BenevolentAI/guacamol
MOSES for the VAE implementation: https://github.com/molecularsets/moses

Data Sources

A key resource to the POLYGON framework is experimental binding data of small molecule ligands. We use the BindingDB as a source for this information, which can be found here: https://www.bindingdb.org/rwd/bind/chemsearch/marvin/Download.jsp

Input molecule training datasets are available from the GuacaMol package: https://github.com/BenevolentAI/guacamol

Installation of POLYGON:

POLYGON has been testing on Python version 3.9.16.

Installation of POLYGON with pip will automatically install the necessary dependencies, which are:

pandas>=1.0.3
numpy>=1.18.1
rdkit>=2019.09.3
torch>=1.4.0
joblib>=0.14.1
scikit-learn>=0.22.1

conda install -c conda-force rdkit
conda install pytorch::pytorch -c pytorch
conda install numpy pandas scikit-learn

git clone https://github.com/bpmunson/polygon.git

cd polygon

pip install .

optionally install cudatoolkit for gpu acceleration in pytorch for example:

conda install cudatoolkit=11.1 -c conda-forge

or see https://pytorch.org/ for specific installation instructions.

Installation time is on the order of minutes.

Example Usage:

Pretrain VAE to encode chemical embedding:

polygon train \
	--train_data ../data/guacamol_v1_train.smiles \
	--log_file log.txt \
	--save_frequency 25 \
	--model_save model.pt \
	--n_epoch 200 \
	--n_batch 1024 \
	--debug \
	--d_dropout 0.2 \
	--device cpu

Train Ligand Binding Models for Two Protein Targets

polygon train_ligand_binding_model \
   --uniprot_id Q02750
   --binding_db_path BindingDB_All.csv
   --output_path Q02750_ligand_binding.pkl

polygon train_ligand_binding_model \
   --uniprot_id P42345
   --binding_db_path BindingDB_All.csv
   --output_path P42345_ligand_binding.pkl

Use the chemical embedding to design polypharmacology compounds

polygon generate \
    --model_path ../data/pretrained_vae_model.pt \
    --scoring_definition scoring_definition.csv \
    --max_len 100 \
    --n_epochs 200 \
    --mols_to_sample 8192   \
    --optimize_batch_size 512    \
    --optimize_n_epochs 2   \
    --keep_top 4096   \
    --opti gauss   \
    --outF molecular_generation   \
    --device cpu  \
    --save_payloads   \
    --n_jobs 4 \
    --debug

The expected runtime for POLYGON is on the order of hours.

POLYGON will output designs as SMILES strings in a text file. For example:

$ head GDM_final_molecules.txt
Fc1cc(F)cc(CC(Nc2ccc3ncccc3c2)c2cccnc2)c1
N[SH](=O)(O)c1cccc(S(=O)(=O)O)c1
N#Cc1cc(C(N)=NO)ccc1Nc1nccc2ccnn12
CN(CN=C(O)c1ccco1)Nc1nccs1