Ligand Binding to PXR

PXR Pocket
The binding pocket of hPXR.


The human pregnane X receptor (hPXR) is a nuclear receptor that binds to various ligands, regulating the breakdown of drugs in the human body. To study drug-drug interactions, we are investigating a method that predicts potential ligand binding conformations in the binding pocket of hPXR.

Binding Conformations from the Geometry of Hydrogen Bonds

The binding pocket of hPXR contains eight polar residues which are key in binding ligands. These polar atoms can potentially share hydrogens with the polar atoms of ligands, forming hydrogen bonds.

A stick for the preferred bond direction from a donor polar atom. Two sticks for the preferred bond directions from an sp2 hybridized acceptor polar atom. A wedge for the preferred bond directions from an sp3 hybridized acceptor polar atom.

Hydrogen bonds have a preferred geometry that depends on the chemical neighborhood of the polar atoms. We model the observed preferred geometry for hydrogen bonding by sticks and wedges. A hydrogen bond is made if two polar atoms are close, and a donor stick is aligned with an acceptor stick or wedge. These geometric constraints are formulated in an optimization problem, whose solutions are ligand conformations that establish at least two hydrogen bonds between a ligand and the binding pocket. We then check the candidate conformations for steric hindrance using a hierarchical collision-detection algorithm and retain the valid conformations in the binding pocket.


  • R.-P. Berretty, D. Hsu, L. Kettner, A. Mascarenhas, M.R. Redinbo, and J. Snoeyink. Ligand binding to the pregnane X receptor by geometric matching of hydrogen bonding. In L. Florea and others, editors, Currents in Computational Molecular Biology, pp. 22–23, 2002. The book contains extended poster abstr acts from RECOMB 2002.



This work has been partially funded by an NSF-ITR grant.