Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites.
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.
Ekins
Sean
S
ACT LLC, 601 Runnymede Avenue, Jenkintown, PA 19046, USA. ekinssean@yahoo.com
Chang
Cheng
C
Mani
Sridhar
S
Krasowski
Matthew D
MD
Reschly
Erica J
EJ
Iyer
Manisha
M
Kholodovych
Vladyslav
V
Ai
Ni
N
Welsh
William J
WJ
Sinz
Michael
M
Swaan
Peter W
PW
Patel
Rachana
R
Bachmann
Kenneth
K
D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D017930:Genes, Reporter; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010957:Plasmids; D000077297:Pregnane X Receptor; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011987:Receptors, Steroid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation
D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D008156:Luciferases