Challenges predicting ligand-receptor interactions of promiscuous proteins: the nuclear receptor PXR.
Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5alpha-androstan-3beta-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches.
Ekins
Sean
S
Collaborations in Chemistry, Jenkintown, Pennsylvania, United States of America. ekinssean@yahoo.com
Kortagere
Sandhya
S
Iyer
Manisha
M
Reschly
Erica J
EJ
Lill
Markus A
MA
Redinbo
Matthew R
MR
Krasowski
Matthew D
MD
D019295:Computational Biology; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D000077297:Pregnane X Receptor; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D011987:Receptors, Steroid / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid