Deep Learning Model for Efficient Protein-Ligand Docking with Implicit Side-Chain Flexibility

J Chem Inf Model. 2023 Mar 27;63(6):1695-1707. doi: 10.1021/acs.jcim.2c01436. Epub 2023 Mar 14.

Abstract

Protein-ligand docking is an essential tool in structure-based drug design with applications ranging from virtual high-throughput screening to pose prediction for lead optimization. Most docking programs for pose prediction are optimized for redocking to an existing cocrystallized protein structure, ignoring protein flexibility. In real-world drug design applications, however, protein flexibility is an essential feature of the ligand-binding process. Flexible protein-ligand docking still remains a significant challenge to computational drug design. To target this challenge, we present a deep learning (DL) model for flexible protein-ligand docking based on the prediction of an intermolecular Euclidean distance matrix (EDM), making the typical use of iterative search algorithms obsolete. The model was trained on a large-scale data set of protein-ligand complexes and evaluated on independent test sets. Our model generates high quality poses for a diverse set of protein and ligand structures and outperforms comparable docking methods.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Deep Learning*
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding
  • Proteins / chemistry
  • Software*

Substances

  • Ligands
  • Proteins