Relative binding affinity prediction of farnesoid X receptor in the D3R Grand Challenge 2 using FEP

J Comput Aided Mol Des. 2018 Jan;32(1):265-272. doi: 10.1007/s10822-017-0064-z. Epub 2017 Sep 12.


Physics-based free energy simulations have increasingly become an important tool for predicting binding affinity and the recent introduction of automated protocols has also paved the way towards a more widespread use in the pharmaceutical industry. The D3R 2016 Grand Challenge 2 provided an opportunity to blindly test the commercial free energy calculation protocol FEP+ and assess its performance relative to other affinity prediction methods. The present D3R free energy prediction challenge was built around two experimental data sets involving inhibitors of farnesoid X receptor (FXR) which is a promising anticancer drug target. The FXR binding site is predominantly hydrophobic with few conserved interaction motifs and strong induced fit effects making it a challenging target for molecular modeling and drug design. For both data sets, we achieved reasonable prediction accuracy (RMSD ≈ 1.4 kcal/mol, rank 3-4 according to RMSD out of 20 submissions) comparable to that of state-of-the-art methods in the field. Our D3R results boosted our confidence in the method and strengthen our desire to expand its applications in future in-house drug design projects.

Keywords: Binding affinity prediction; Computer-aided drug design; D3R; Drug design data resource; Free energy calculations.

MeSH terms

  • Binding Sites
  • Computer-Aided Design
  • Drug Design*
  • Humans
  • Ligands
  • Molecular Docking Simulation*
  • Protein Binding
  • Protein Conformation
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Thermodynamics*


  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Small Molecule Libraries
  • farnesoid X-activated receptor