Hybrid scoring and classification approaches to predict human pregnane X receptor activators

Pharm Res. 2009 Apr;26(4):1001-11. doi: 10.1007/s11095-008-9809-7. Epub 2008 Dec 30.


Purpose: The human pregnane X receptor (PXR) is a transcriptional regulator of many genes involved in xenobiotic metabolism and excretion. Reliable prediction of high affinity binders with this receptor would be valuable for pharmaceutical drug discovery to predict potential toxicological responses

Materials and methods: Computational models were developed and validated for a dataset consisting of human PXR (PXR) activators and non-activators. We used support vector machine (SVM) algorithms with molecular descriptors derived from two sources, Shape Signatures and the Molecular Operating Environment (MOE) application software. We also employed the molecular docking program GOLD in which the GoldScore method was supplemented with other scoring functions to improve docking results.

Results: The overall test set prediction accuracy for PXR activators with SVM was 72% to 81%. This indicates that molecular shape descriptors are useful in classification of compounds binding to this receptor. The best docking prediction accuracy (61%) was obtained using 1D Shape Signature descriptors as a weighting factor to the GoldScore. By pooling the available human PXR data sets we revealed those molecular features that are associated with human PXR activators.

Conclusions: These combined computational approaches using molecular shape information may assist scientists to more confidently identify PXR activators.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Binding Sites
  • Computer Simulation
  • Computer-Aided Design*
  • Crystallography, X-Ray
  • Databases, Protein
  • Drug Design*
  • Humans
  • Ligands
  • Models, Molecular*
  • Molecular Structure
  • Pregnane X Receptor
  • Protein Conformation
  • Receptors, Steroid / agonists
  • Receptors, Steroid / chemistry*
  • Reproducibility of Results
  • Structure-Activity Relationship


  • Ligands
  • Pregnane X Receptor
  • Receptors, Steroid