Journal of Computer-Aided Molecular Design

, Volume 29, Issue 5, pp 421–439 | Cite as

Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands

  • Stephanie N. Lewis
  • Zulma Garcia
  • Raquel Hontecillas
  • Josep Bassaganya-Riera
  • David R. Bevan
Article

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear hormone receptor involved in regulating various metabolic and immune processes. The PPAR family of receptors possesses a large binding cavity that imparts promiscuity of ligand binding not common to other nuclear receptors. This feature increases the challenge of using computational methods to identify PPAR ligands that will dock favorably into a structural model. Utilizing both ligand- and structure-based pharmacophore methods, we sought to improve agonist prediction by grouping ligands according to pharmacophore features, and pairing models derived from these features with receptor structures for docking. For 22 of the 33 receptor structures evaluated we observed an increase in true positive rate (TPR) when screening was restricted to compounds sharing molecular features found in rosiglitazone. A combination of structure models used for docking resulted in a higher TPR (40 %) when compared to docking with a single structure model (<20 %). Prediction was also improved when specific protein–ligand interactions between the docked ligands and structure models were given greater weight than the calculated free energy of binding. A large-scale screen of compounds using a marketed drug database verified the predictive ability of the selected structure models. This study highlights the steps necessary to improve screening for PPARγ ligands using multiple structure models, ligand-based pharmacophore data, evaluation of protein–ligand interactions, and comparison of docking datasets. The unique combination of methods presented here holds potential for more efficient screening of compounds with unknown affinity for PPARγ that could serve as candidates for therapeutic development.

Keywords

Virtual screening Computational molecular docking PPARγ Pharmacophore modeling Drug discovery and design 

Supplementary material

10822_2015_9831_MOESM1_ESM.docx (75 kb)
Supplementary material 1 (DOCX 74 kb)
10822_2015_9831_MOESM2_ESM.docx (94 kb)
Supplementary material 2 (DOCX 94 kb)
10822_2015_9831_MOESM3_ESM.docx (23 kb)
Supplementary material 3 (DOCX 23 kb)

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Stephanie N. Lewis
    • 1
    • 2
    • 4
  • Zulma Garcia
    • 3
  • Raquel Hontecillas
    • 1
    • 4
  • Josep Bassaganya-Riera
    • 1
    • 4
    • 5
  • David R. Bevan
    • 1
    • 2
  1. 1.Genetics, Bioinformatics, and Computational Biology ProgramVirginia TechBlacksburgUSA
  2. 2.Department of BiochemistryVirginia TechBlacksburgUSA
  3. 3.Virginia College of Osteopathic MedicineVirginia TechBlacksburgUSA
  4. 4.Nutritional Immunology and Molecular Medicine Laboratory, Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics InstituteVirginia TechBlacksburgUSA
  5. 5.Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary MedicineVirginia TechBlacksburgUSA

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