CENsible 1.2

Introduction

CENsible uses deep-learning context explanation networks (CENs) to predict small-molecule binding affinities. Rather than predict a binding affinity directly, it predicts the contributions of pre-calculated terms to the overall affinity, thus providing interpretable output. CENsible insights are useful for subsequent lead optimization.

We release CENsible under the terms of the GNU General Public License v3.0. The git repository is available at https://github.com/durrantlab/censible. A Google Colab is also available for easy testing.

These instructions describe how to use CENsible for inference (prediction). If you wish to train your own CENsible model, see train/README.md for some tips.

Installation

1. Install Python

We recommend using anaconda python to create a new environment. We have tested CENsible on Python 3.9.16.

conda create -n censible python=3.9.16
conda activate censible

2. Clone the Repository

git clone https://github.com/durrantlab/censible.git
cd censible

3. Install Dependencies

If you wish only to use CENsible for inference (prediction), install the dependencies in the requirements_predict.txt file:

pip install -r requirements_predict.txt

NOTE: If you don't have CUDA installed on your system, you may need to edit the requirements_predict.txt file to install the CPU version of PyTorch. If so, run the censible script using the --use_cpu flag (see below).

4. Install smina

CENsible uses smina to calculate the pre-calculated terms. Visit the smina website to download the latest version.

You can also install smina using Anaconda:

conda install -c conda-forge smina

We used the Oct 15 2019 version of smina (based onAutoDock Vina 1.1.2) to calculate terms for testing and training, though we expect other versions will work equally well.

5. Install Open Babel

CENsible uses Open Babel to standardize the user-provided protein and small-molecule files. Visit the Open Babel repository to download the latest version.

You can also install Open Babel using Anaconda:

conda install -c conda-forge openbabel

We used Open Babel 3.0.0 (Mar 11 2020) for training and testing. We rescored the virtual screens described in our manuscript using Babel 3.1.0 (Oct 28 2022), which also worked well.

6. Test the CENsible Installation

To test the installation, run the following command:

./test_predict.sh

NOTE: This script assumes smina and obaebl are in your PATH. Additionally, if you have installed a version of Pytorch that does not support CUDA, you must edit the test_predict.sh file to add the --use_cpu flag.

Usage

Simple Use

Here is a simple example of how to use CENsible for inference (prediction):

python predict.py --ligpath censible/data/test/1wdn_ligand.mol2 \
                  --recpath censible/data/test/1wdn_receptor.pdb \
                  --smina_exec_path /usr/local/bin/smina \
                  --obabel_exec_path /usr/local/bin/obabel

NOTE: You should replace the --ligpath and --recpath arguments with the path to your ligand and receptor files, respectively. You should also replace the --smina_exec_path and --obabel_exec_path arguments with the paths to your smina and obabel executables, respectively.

Saving CENsible Weights

In the above simple example, CENsible only outputs the predicted affinity. If you also wish to output CENsible's predicted weights (as well as other information used to calculate the final score), use the --tsv_out flag:

python predict.py --ligpath censible/data/test/1wdn_ligand.mol2 \
                  --recpath censible/data/test/1wdn_receptor.pdb \
                  --smina_exec_path /usr/local/bin/smina \
                  --obabel_exec_path /usr/local/bin/obabel \
                  --tsv_out test_out.tsv

CENsible will output affinity to test_out.tsv, an Excel-compatible tab-delimited file. It will also output the following additional information:

• A text description of the pre-calculated terms the model uses.
• The pre-calculated terms themselves (calculated using smina).
• The pre-calculated terms after scaling/normalization.
• The weights the model assigns to each pre-calculated term.
• The predicted contribution of each pre-calculated term to the overall affinity (i.e., the product of the normalized pre-calculated term and its weight).

NOTE: The final affinity is the sum of the predicted contributions.

Saving Per-Atom Gaussian Steric Terms to a PDB File

CENsible can also output the per-atom contributions associated with smina's Gaussian steric (atom_type_gaussian) terms to a PDB file. Use the --pdb_out flag. For example:

python predict.py --ligpath censible/data/test/1wdn_ligand.mol2 \
                  --recpath censible/data/test/1wdn_receptor.pdb \
                  --smina_exec_path /usr/local/bin/smina \
                  --obabel_exec_path /usr/local/bin/obabel \
                  --tsv_out test_out.tsv \
                  --pdb_out test_out.pdb

The per-atom terms are placed in the beta column. See the HEADER fields of the output PDB file for additional useful information.

Using Other CENsible Models

CENsible comes with a pre-trained model (described in the accompanying manuscript, see censible/data/model_allcen3/). If you wish to use your own model, specify the path to the model directory using the --model_dir flag:

python predict.py --ligpath censible/data/test/1wdn_ligand.mol2 \
                  --recpath censible/data/test/1wdn_receptor.pdb \
                  --smina_exec_path /usr/local/bin/smina \
                  --obabel_exec_path /usr/local/bin/obabel \
                  --model_dir ./my_model_dir/ \
                  --tsv_out test_out.tsv

The model directory should contain the following files:

• model.pt: The trained model.
• precalc_term_scales.npy: The pre-calculated term scales.
• which_precalc_terms_to_keep.npy: The pre-calculated terms the model uses.