Attenuating pregnane X receptor (PXR) activation: A molecular modelling approach

Recent studies have demonstrated that the pregnane X receptor (PXR) is a key regulator of cytochromes P450 3A (e.g. CYP3A4 in human) gene expression. As a result, activation of PXR may lead to CYP3A4 protein over-expression. Because induction of CYP3A4 could result in clinically important drug–drug interactions, there has been a great interest in reducing the possibility of PXR activation by drug candidates in drug-discovery programmes. In order to provide structural insight for attenuating drug candidate-mediated PXR activation, we used a docking approach to study the structure–activity relationship for PXR activators. Based on our docking models, it is proposed that introducing polar groups to the end of an activator should reduce its human PXR (hPXR) activity via destabilizing interactions in the hydrophobic areas of the PXR ligand-binding pocket. A number of analogues that incorporate these structural features then were designed and synthesized, and they exhibited significantly lower hPXR activation in a transactivation assay and decreased CYP3A4 induction in a human hepatocytes-based assay. In addition, an example in which attenuating hPXR activation was achieved by sterically destabilizing the helices 11 and 12 of the receptor is presented.

[1]  Toshiyuki Shimizu,et al.  AUTOINDUCTION OF MKC-963 [(R)-1-(1-CYCLOHEXYLETHYLAMINO)-4-PHENYLPHTHALAZINE] METABOLISM IN HEALTHY VOLUNTEERS AND ITS RETROSPECTIVE EVALUATION USING PRIMARY HUMAN HEPATOCYTES AND CDNA-EXPRESSED ENZYMES , 2006, Drug Metabolism and Disposition.

[2]  Michael Rowley,et al.  Potent inhibitors of subgenomic hepatitis C virus RNA replication through optimization of indole-N-acetamide allosteric inhibitors of the viral NS5B polymerase. , 2005, Journal of medicinal chemistry.

[3]  L. Moore,et al.  Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. , 2005, Molecular endocrinology.

[4]  Thierry Langer,et al.  The Identification of Ligand Features Essential for PXR Activation by Pharmacophore Modeling , 2005, J. Chem. Inf. Model..

[5]  W. Humphreys,et al.  CYP3A4 induction by xenobiotics: biochemistry, experimental methods and impact on drug discovery and development. , 2004, Current drug metabolism.

[6]  H. Bolt.  Rifampicin, A Keystone Inducer of Drug Metabolism: From Herbert Remmer's Pioneering Ideas to Modern Concepts , 2004, Drug metabolism reviews.

[7]  M. Lambert,et al.  Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. , 2003, Journal of molecular biology.

[8]  L. Moore,et al.  2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. , 2003, Biochemistry.

[9]  L. Jendeberg,et al.  Identification of residues in the PXR ligand binding domain critical for species specific and constitutive activation. , 2002, European journal of biochemistry.

[10]  Sean Ekins,et al.  A pharmacophore for human pregnane X receptor ligands. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[11]  L. Moore,et al.  The Human Nuclear Xenobiotic Receptor PXR: Structural Determinants of Directed Promiscuity , 2001, Science.

[12]  E. Schuetz.  Induction of cytochromes P450. , 2001, Current drug metabolism.

[13]  P. Guzelian,et al.  Cyp3A regulation: from pharmacology to nuclear receptors. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[14]  Michael D. Miller,et al.  Comparison of Knowledge-Based and Distance Geometry Approaches for Generation of Molecular Conformations , 2001, J. Chem. Inf. Comput. Sci..

[15]  S. Kliewer,et al.  Use of the nuclear receptor PXR to predict drug interactions. , 2000, Toxicology.

[16]  R. Stocco,et al.  A reporter gene assay for high-throughput screening of G-protein-coupled receptors stably or transiently expressed in HEK293 EBNA cells grown in suspension culture. , 2000, Analytical biochemistry.

[17]  B. Neuschwander‐Tetri,et al.  Humanized xenobiotic response in mice expressing nuclear receptor SXR , 2000, Nature.

[18]  L. Moore,et al.  St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[19]  L. Moore,et al.  The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. , 2000, Molecular endocrinology.

[20]  T. Halgren.  MMFF VI. MMFF94s option for energy minimization studies , 1999, J. Comput. Chem..

[21]  R. Sheridan,et al.  SQ: a program for rapidly producing pharmacophorically relevent molecular superpositions. , 1999, Journal of medicinal chemistry.

[22]  F. Guengerich,et al.  Cytochrome P-450 3A4: regulation and role in drug metabolism. , 1999, Annual review of pharmacology and toxicology.

[23]  W. Sabbagh,et al.  SXR, a novel steroid and xenobiotic-sensing nuclear receptor. , 1998, Genes & development.

[24]  R Ohlsson,et al.  Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Lehmann,et al.  The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. , 1998, The Journal of clinical investigation.

[26]  J. Lehmann,et al.  An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway , 1998, Cell.

[27]  István Kolossváry,et al.  Low Mode Search . An Efficient , Automated Computational Method for Conformational Analysis : Application to Cyclic and Acyclic Alkanes and Cyclic Peptides , 1997 .

[28]  F. A. Neugebauer,et al.  Electrochemical oxidation and structural changes of 5,6-dihydrobenzo[c]cinnolines , 1996 .

[29]  S. Shoaf,et al.  Ethanol Induces CYP2E1 by Protein Stabilization , 1995, The Journal of Biological Chemistry.

[30]  S. Shoaf,et al.  Ethanol Induces CYP2E1 by Protein Stabilization ROLE OF UBIQUITIN CONJUGATION IN THE RAPID DEGRADATION OF CYP2E1* , 1995 .