Explainable Machine Learning and Deep Learning Models for Predicting TAS2R-Bitter Molecule Interactions

TL;DR

This paper develops and combines machine learning and deep learning models to predict and explain interactions between bitter molecules and TAS2R receptors, aiding taste perception understanding and drug design.

Contribution

It introduces high-performance, explainable ML and DL models for TAS2R ligand prediction, integrating methods to improve interpretability and molecular understanding.

Findings

Models achieve high predictive accuracy.

Combined models enhance explainability.

Facilitates design of targeted bitter compounds.

Abstract

This work aims to develop explainable models to predict the interactions between bitter molecules and TAS2Rs via traditional machine-learning and deep-learning methods starting from experimentally validated data. Bitterness is one of the five basic taste modalities that can be perceived by humans and other mammals. It is mediated by a family of G protein-coupled receptors (GPCRs), namely taste receptor type 2 (TAS2R) or bitter taste receptors. Furthermore, TAS2Rs participate in numerous functions beyond the gustatory system and have implications for various diseases due to their expression in various extra-oral tissues. For this reason, predicting the specific ligand-TAS2Rs interactions can be useful not only in the field of taste perception but also in the broader context of drug design. Considering that in-vitro screening of potential TAS2R ligands is expensive and time-consuming, machine learning (ML) and deep learning (DL) emerged as powerful tools to assist in the selection of ligands and targets for experimental studies and enhance our understanding of bitter receptor roles. In this context, ML and DL models developed in this work are both characterized by high performance and easy applicability. Furthermore, they can be synergistically integrated to enhance model explainability and facilitate the interpretation of results. Hence, the presented models promote a comprehensive understanding of the molecular characteristics of bitter compounds and the design of novel bitterants tailored to target specific TAS2Rs of interest.