Featurization strategies for protein–ligand interactions and their applications in scoring function development

Guoli Xiong, Chao Shen, Ziyi Yang, Dejun Jiang, Shao Liu, Aiping Lu, Xiang Chen*, Tingjun Hou*, Dongsheng Cao*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

30 Citations (Scopus)


The predictive performance of classical scoring functions (SFs) seems to have reached a plateau. Currently, SFs relying on sophisticated machine learning techniques have shown great potential in binding affinity prediction and virtual screening. As one of the most indispensable components in the workflow of training a machine learning scoring function (MLSF), the featurization or representation process enables us to catch certain physical processes that are important for protein–ligand interactions and to obtain machine-readable descriptors. Currently, according to how they are derived, the descriptors used in MLSFs for both continuous and binary binding affinity estimates can be grouped into two broad categories: handcrafted features and automated-extraction features. Moreover, the automated-extraction features emerge as a new featurization trend along with the application of deep learning algorithms. Here, we make a thorough summary of the advances in the featurization strategies for protein–ligand interactions in the context of MLSFs, with emphasis on the recently rising automated-extraction features. We also discuss the similarity between protein–ligand interaction representations and small-molecule representations, and the challenges confronted by the scientific community in characterizing protein–ligand interactions. We expect that this review could inspire the development of novel featurization approaches and boosted MLSFs.

This article is categorized under: Data Science > Artificial Intelligence/Machine Learning Software > Molecular Modeling Molecular and Statistical Mechanics > Molecular Interactions.

Original languageEnglish
Article numbere1567
JournalWiley Interdisciplinary Reviews: Computational Molecular Science
Issue number2
Early online date3 Aug 2021
Publication statusPublished - Mar 2022

Scopus Subject Areas

  • Biochemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Computational Mathematics
  • Materials Chemistry

User-Defined Keywords

  • artificial intelligence
  • feature engineering
  • machine learning
  • protein–ligand interaction
  • scoring functions


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