visar 0.3.8

This project aims to train neural networks by compound-protein interactions and provides interpretation of the learned model by interactively showing transformed chemical landscape and visualized SAR for chemicals of interest.

VISAR

VISAR: an interactive tool for dissecting chemical features learned by deep neural network QSAR models

Qingyang Ding, Siyu Hou, Songpeng Zu, Yonghui Zhang, Shao Li

Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing 100084, China

School of Pharmaceutical Science, Tsinghua University, Beijing 100084, China.

Please contact [e-mail] if you have question or suggestions.

Table of contents

• Aims of this project
• Workflow
• Usage instructions

Aims of this project

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While many previous works focus on improving predictive merits of the models, few looked into the trained model and check if the model is learning what's truly important, as well as link what have been learned by the model back to useful insights.

Here we took a step forward to interpret the learned features from deep neural network QSAR models, and present VISAR, an interactive tool for visualizing structure-activity relationship and the chemical activity landscape based on the learned features, thus providing deeper insights of the neural network 'black-box'. For a learning task, VISAR firstly provided users with useful functions to build, train and test the deep neural network models.

The rationale of VISAR workflow is shown in the schematic diagram below:

Starting from a series of trained weights of the neural network QSAR models, VISAR provided visualization tools for dissecting the learned chemical features on 3 levels: 1) on the macro-level, compounds with weighted features are clustered and forming different chemical landscapes regarding different tasks; 2) on the meso-level, within each local cluster of chemicals on the chemical landscape sharing similar sturcture and similar activity, pharmacophoric features could be identified; 3) on the micro-level, the SAR pattern is built for each compound regarding each task.

The VISAR workflow features:

• For a learning task, VISAR firstly provided users with useful functions to build, train and test the neural network models.
• The learned parameters of the models were then mapped back as weights of each atom and were visualized as structural-activity relationship (SAR) patterns, demonstrating the positive and negative contributor substructure suggested by the trained model.
• VISAR took the transformed features of the chemicals and build activity landscapes, showing the correlation between the descriptor space after model training and the experimental activity space.
• With the interactive web application of VISAR, users could interactively explore the chemical space and the SAR pattern for each chemical.
• Users could provide their compounds of interest, and predict target profiles with the trained model, as well as map them on the chemical space for further analysis.
• The clusters of chemicals on the landscape could be then subject to analysis of active pharmacophores.

We proposed that VISAR could serve as a helpful workflow for training and interactive analysis of the deep neural network QSAR model.

Workflow

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The training, testing and result processing pipeline is available in template jupyter notebooks:

• Train single task regression model
• Train robust multitask regression model

After the train process, start the app in prompt window by 'bokeh serve --show VISAR_webapp' for interactive exploration.

The general steps for interactive analysis are:

• Set the location (including the prefix) of the pre-composed dataframes and the mode of your training. After clicking "Run" button on the upper panel, the whole interface would update according to your settings.

  • For single task sample dataset, set "Prefix of the input data:" as 'VISAR_webapp/data/T107_rep2_50_' with 'Mode of the model:' as 'ST', and then click "Run";
  • For multitask sample dataset, set 'Prefix of the input data:' as 'VISAR_webapp/data/output_' with 'Mode of the model:' as 'RobustMT', and then click "Run".

• Explore the activity profile of the chemical space on the left panel. There are several places allowing for interactive exploring, including: A. color options for the scatter plotting, enabling different color rendering based on eg. different activity of the compounds; B. number of bi-clusters, which correlated with the arrangement of the heatmap on the bottom panel (through trying out different bi-cluster numbers, users could gain an idea of how the activity profile is distributed on the chemical landscape); E. information fo the compounds when hovering your mouse on the scatter plot, displaying its ID, batch ID and the color code for the bi-cluster where it belongs; F. information of the batch when hovering your mouse on the heatmap, displaying its ID and color code for the bi-cluster where it belongs.

• Upon selecting the batch or indivisual compounds on the left panel, visualize chemical structures along with the SAR pattern on the right panel. There are two ways for batch selection: first is to directly click on the heatmap, second is to use the drop-down list (C). As for compound selection, use the tap mode of the scatter plot and click on the points. Since for RobustMT mode, multiple tasks give their corresponding SAR patterns for the compound; thus by selecting SAR task (D), the SAR pattern of the compounds would update accordingly.

The generation of SDF file for selected compounds and pharmacophor analysis can be referred to the template jupyter notebook.

Usage instructions

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1. Get your local copy of the VISAR repository (including the template jupyter notebooks) by

• downloading it as zip archive and unzipping it:

• OR cloning it to your computer using the package git:

git clone https://github.com/Svvord/visar.git

2. Preparing the working environment for visualization using Conda is recommended, and is referred to TeachOpenCADD.

# Create and activate an environment called `visar`
conda create -n visar python=3.6
conda activate visar

# Install packages via conda
conda install bokeh
conda install -c rdkit rdkit  # Installs also numpy and pandas
conda install -c conda-forge scikit-learn  # Installs also scipy
conda install jupyter  # Installs also ipykernel
conda install -c conda-forge seaborn  # Installs also matplotlib
conda install -c conda-forge cairosvg
conda install -c samoturk pymol  # optional
conda install -c conda-forge pmw  # optional

# start the web app
cd /path/of/visar
bokeh serve --show VISAR_webapp

3. For training environment, python=3.5 is recommended, and the environment is depended on: Deepchem, Rdkit, Keras, Tensorflow, Numpy, Pandas, Sklearn, Scipy.

# Install packages via pip
pip install visar