Journal article
Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites
Molecular pharmacology, Vol.72(3), pp.592-603
09/2007
DOI: 10.1124/mol.107.038398
PMID: 17576789
Abstract
The pregnane X receptor (PXR) is an important transcriptional regulator of the expression of xenobiotic metabolism and transporter genes. The receptor is promiscuous, binding many structural classes of molecules that act as agonists at the ligand-binding domain, triggering up-regulation of genes, increasing the metabolism and excretion of therapeutic agents, and causing drug-drug interactions. It has been suggested that human PXR antagonists represent a means to counteract such interactions. Several azoles have been hypothesized to bind the activation function-2 (AF-2) surface on the exterior of PXR when agonists are concurrently bound in the ligand-binding domain. In the present study, we have derived novel computational models for PXR agonists using different series of imidazoles, steroids, and a set of diverse molecules with experimental PXR agonist binding data. We have additionally defined a novel pharmacophore for the steroidal agonist site. All agonist pharmacophores showed that hydrophobic features are predominant. In contrast, a qualitative comparison with the corresponding PXR antagonist pharmacophore models using azoles and biphenyls showed that they are smaller and hydrophobic with increased emphasis on hydrogen bonding features. Azole antagonists were docked into a proposed hydrophobic binding pocket on the outer surface at the AF-2 site and fitted comfortably, making interactions with key amino acids involved in charge clamping. Combining computational and experimental data for different classes of molecules provided strong evidence for agonists and antagonists binding distinct regions on PXR. These observations bear significant implications for future discovery of molecules that are more selective and potent antagonists.
Details
- Title: Subtitle
- Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites
- Creators
- Sean Ekins - ACT LLC, 601 Runnymede Avenue, Jenkintown, PA 19046, USA. ekinssean@yahoo.comCheng ChangSridhar ManiMatthew D KrasowskiErica J ReschlyManisha IyerVladyslav KholodovychNi AiWilliam J WelshMichael SinzPeter W SwaanRachana PatelKenneth Bachmann
- Resource Type
- Journal article
- Publication Details
- Molecular pharmacology, Vol.72(3), pp.592-603
- Publisher
- United States
- DOI
- 10.1124/mol.107.038398
- PMID
- 17576789
- ISSN
- 0026-895X
- eISSN
- 1521-0111
- Grant note
- K08 GM074238-01A1 / NIGMS NIH HHS K08 GM074238-02 / NIGMS NIH HHS K08-GM074238 / NIGMS NIH HHS
- Language
- English
- Date published
- 09/2007
- Academic Unit
- Pathology
- Record Identifier
- 9984047740802771
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