title: Ligand- and structure-based pregnane X receptor models.
abstract: The human pregnane X receptor (PXR) is a ligand dependent transcription factor that can be activated by structurally diverse agonists including steroid hormones, bile acids, herbal drugs, and prescription medications. PXR regulates the transcription of several genes involved in xenobiotic detoxification and apoptosis. Activation of PXR has the potential to initiate adverse effects by altering drug pharmacokinetics or perturbing physiological processes. Hence, more reliable prediction of PXR activators would be valuable for pharmaceutical drug discovery to avoid potential toxic effects. Ligand- and protein structure-based computational models for PXR activation have been developed in several studies. There has been limited success with structure-based modeling approaches to predict human PXR activators, which can be attributed to the large and promiscuous site of this protein. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning that use appropriate descriptors to account for the diversity of the ligand classes that bind to PXR. These combined computational approaches using molecular shape information may assist scientists to more confidently identify PXR activators. This chapter reviews the various ligand and structure based methods undertaken to date and their results.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA. Sandhya.Kortagere@drexelmed.edu
authors.forename: Sandhya
authors.initials: S
authors.lastname: Kortagere
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Krasowski
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
mesh_terms: D001499:Bayes Theorem; D006801:Humans; D008958:Models, Molecular; D000077297:Pregnane X Receptor; D021281:Quantitative Structure-Activity Relationship; D011987:Receptors, Steroid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D060388:Support Vector Machine
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid