Three-dimensional quantitative structure-activity relationship analysis for human pregnane X receptor for the prediction of CYP3A4 induction in human hepatocytes: structure-based comparative molecular field analysis

J Pharm Sci. 2015 Jan;104(1):223-32. doi: 10.1002/jps.24235. Epub 2014 Nov 7.


The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand-protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process.

Keywords: QSAR; computational ADME; molecular modeling; protein structure; structure activity relationship (SAR).

Publication types

  • Validation Study

MeSH terms

  • Artificial Intelligence
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inducers / chemistry
  • Cytochrome P-450 CYP3A Inducers / metabolism
  • Cytochrome P-450 CYP3A Inducers / pharmacology*
  • Databases, Protein
  • Drug Discovery / methods*
  • Energy Transfer
  • Enzyme Induction / drug effects
  • Expert Systems
  • Hepatocytes / drug effects*
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Imaging, Three-Dimensional
  • Ligands
  • Models, Molecular*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Pregnane X Receptor
  • Protein Conformation
  • Quantitative Structure-Activity Relationship
  • Receptors, Steroid / agonists*
  • Receptors, Steroid / chemistry
  • Receptors, Steroid / metabolism
  • Reproducibility of Results


  • Cytochrome P-450 CYP3A Inducers
  • Ligands
  • NR1I2 protein, human
  • Pregnane X Receptor
  • Receptors, Steroid
  • Cytochrome P-450 CYP3A