DeepSIBA: chemical structure-based inference of biological alterations using deep learning

Mol Omics. 2021 Feb 1;17(1):108-120. doi: 10.1039/d0mo00129e. Epub 2020 Nov 14.

Abstract

Predicting whether a chemical structure leads to a desired or adverse biological effect can have a significant impact for in silico drug discovery. In this study, we developed a deep learning model where compound structures are represented as graphs and then linked to their biological footprint. To make this complex problem computationally tractable, compound differences were mapped to biological effect alterations using Siamese Graph Convolutional Neural Networks. The proposed model was able to encode molecular graph pairs and identify structurally dissimilar compounds that affect similar biological processes with high precision. Additionally, by utilizing deep ensembles to estimate uncertainty, we were able to provide reliable and accurate predictions for chemical structures that are very different from the ones used during training. Finally, we present a novel inference approach, where the trained models are used to estimate the signaling pathway signature of a compound perturbation, using only its chemical structure as input, and subsequently identify which substructures influenced the predicted pathways. As a use case, this approach was used to infer important substructures and affected signaling pathways of FDA-approved anticancer drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Deep Learning*
  • Drug Discovery / methods*
  • Humans
  • Neural Networks, Computer*
  • Software*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents