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Human Pregnane X Receptor Antagonists and Agonists Define Molecular Requirements for Different Binding Sites

ACT LLC, Jenkintown, Pennsylvania (S.E.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (S.E., C.C., P.W.S.); Albert Einstein Cancer Center and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.); Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (M.D.K., E.J.R., M.I.); Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey (V.K., N.A., W.J.W.); Bristol-Myers Squibb Company, Research Parkway, Wallingford, Connecticut (M.S.); and Department of Pharmacology, The University of Toledo, Toledo,Ohio (R.P., K.B.)

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.

Address correspondence to: Dr. Sean Ekins, ACT LLC, 601 Runnymede Avenue, Jenkintown, PA 19046. E-mail: ekinssean{at}yahoo.com

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