当前位置： SCI文献检索 > MOLECULAR PHARMACOLOGY期刊下所有文献 > Computational discovery of novel low micromolar human pregnane X receptor antagonists.

Computational discovery of novel low micromolar human pregnane X receptor antagonists.

Abstract：

:Very few antagonists have been identified for the human pregnane X receptor (PXR). These molecules may be of use for modulating the effects of therapeutic drugs, which are potent agonists for this receptor (e.g., some anticancer compounds and macrolide antibiotics), with subsequent effects on transcriptional regulation of xenobiotic metabolism and transporter genes. A recent novel pharmacophore for PXR antagonists was developed using three azoles and consisted of two hydrogen bond acceptor regions and two hydrophobic features. This pharmacophore also suggested an overall small binding site that was identified on the outer surface of the receptor at the AF-2 site and validated by docking studies. Using computational approaches to search libraries of known drugs or commercially available molecules is preferred over random screening. We have now described several new smaller antagonists of PXR discovered with the antagonist pharmacophore with in vitro activity in the low micromolar range [S-p-tolyl 3',5-dimethyl-3,5'-biisoxazole-4'-carbothioate (SPB03255) (IC(50), 6.3 microM) and 4-(3-chlorophenyl)-5-(2,4-dichlorobenzylthio)-4H-1,2,4-triazol-3-ol (SPB00574) (IC(50), 24.8 microM)]. We have also used our computational pharmacophore and docking tools to suggest that most of the known PXR antagonists, such as coumestrol and sulforaphane, could also interact on the outer surface of PXR at the AF-2 domain. The involvement of this domain was also suggested by further site-directed mutagenesis work. We have additionally described an FDA approved prodrug, leflunomide (IC(50), 6.8 microM), that seems to be a PXR antagonist in vitro. These observations are important for predicting whether further molecules may interact with PXR as antagonists in vivo with potential therapeutic applications.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Ekins S,Kholodovych V,Ai N,Sinz M,Gal J,Gera L,Welsh WJ,Bachmann K,Mani S

doi

10.1124/mol.108.049437

subject

Has Abstract

pub_date

2008-09-01 00:00:00

pages

662-72

issue

3

eissn

0026-895X

issn

1521-0111

pii

mol.108.049437

journal_volume

74

pub_type

杂志文章

相关文献

MOLECULAR PHARMACOLOGY文献大全
  • Identification and characterization of a potent activator of p53-independent cellular senescence via a small-molecule screen for modifiers of the integrated stress response.

    abstract：:The Integrated Stress Response (ISR) is a signaling program that enables cellular adaptation to stressful conditions like hypoxia and nutrient deprivation in the tumor microenvironment. An important effector of the ISR is activating transcription factor 4 (ATF4), a transcription factor that regulates genes involved in...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.112.081810

    authors： Sayers CM,Papandreou I,Guttmann DM,Maas NL,Diehl JA,Witze ES,Koong AC,Koumenis C

    更新日期：2013-03-01 00:00:00

  • Inhibition of cyclic AMP-dependent kinase by expression of a protein kinase inhibitor/enhanced green fluorescent fusion protein attenuates angiotensin II-induced type 1 AT1 receptor mRNA down-regulation in vascular smooth muscle cells.

    abstract：:Expression of the angiotensin II type 1 receptor (AT1-R) mRNA in vascular smooth muscle cells (VSMC) is down-regulated by a variety of agonists, including growth factors, agonists of Galphaq protein-coupled receptors, and activators of adenylyl cyclase. To determine whether cAMP-dependent protein kinases (PKA) partici...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.54.3.514

    authors： Wang X,Murphy TJ

    更新日期：1998-09-01 00:00:00

  • Functional interactions between nucleotide binding domains and leukotriene C4 binding sites of multidrug resistance protein 1 (ABCC1).

    abstract：:Multidrug resistance protein 1 (MRP1) is a member of the "C" branch of the ATP-binding cassette transporter superfamily. The NH(2)-proximal nucleotide-binding domain (NBD1) of MRP1 differs functionally from its COOH-proximal domain (NBD2). NBD1 displays intrinsic high-affinity ATP binding and little ATPase activity. I...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.104.007708

    authors： Payen L,Gao M,Westlake C,Theis A,Cole SP,Deeley RG

    更新日期：2005-06-01 00:00:00

  • Inhibition of capacitative Ca2+ entry into cells by farnesylcysteine analogs.

    abstract：:Capacitative Ca2+ influx, which occurs in response to mobilization of intracellular Ca2+ stores, is a general feature of many cell types. Although the mechanism of capacitative Ca2+ entry is not known, evidence suggests the involvement of small G proteins that are prenylated on a cysteine residue near their carboxyl t...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Xu Y,Gilbert BA,Rando RR,Chen L,Tashjian AH Jr

    更新日期：1996-12-01 00:00:00

  • Desensitization of NO/cGMP signaling in smooth muscle: blood vessels versus airways.

    abstract：:The NO/cGMP signaling pathway plays a major role in the cardiovascular system, in which it is involved in the regulation of smooth muscle tone and inhibition of platelet aggregation. Under pathophysiological conditions such as endothelial dysfunction, coronary artery disease, and airway hyperreactivity, smooth muscle ...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.105.020909

    authors： Mullershausen F,Lange A,Mergia E,Friebe A,Koesling D

    更新日期：2006-06-01 00:00:00

  • Hemin administration to rats reduces levels of hepatic mRNAs for phenobarbitone-inducible enzymes.

    abstract：:The levels of hepatic mRNAs for several enzymes involved in drug metabolism were measured following administration to rats of either phenobarbitone or 2-allyl-2-isopropylacetamide. There was a substantial elevation in the mRNA levels for cytochromes P450 IIB1, IIB2, and IIIA1, epoxide hydrolase, glutathione-S-transfer...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Srivastava G,Hansen AJ,Bawden MJ,May BK

    更新日期：1990-10-01 00:00:00

  • Activation of human ether-a-go-go-related gene potassium channels by the diphenylurea 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643).

    abstract：:The cardiac action potential is generated by a concerted action of different ion channels and transporters. Dysfunction of any of these membrane proteins can give rise to cardiac arrhythmias, which is particularly true for the repolarizing potassium channels. We suggest that an increased repolarization current could b...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.105.015859

    authors： Hansen RS,Diness TG,Christ T,Demnitz J,Ravens U,Olesen SP,Grunnet M

    更新日期：2006-01-01 00:00:00

  • Efficacy as a vector: the relative prevalence and paucity of inverse agonism.

    abstract：:This article describes the expected phenotypic behavior of all types of ligands in constitutively active receptor systems and, in particular, the molecular mechanisms of inverse agonism. The possible physiological relevance of inverse agonism also is discussed. Competitive antagonists with the molecular property of ne...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章,评审

    doi：10.1124/mol.65.1.2

    authors： Kenakin T

    更新日期：2004-01-01 00:00:00

  • Niemann-pick C1-like 1 mediates alpha-tocopherol transport.

    abstract：:Dietary lipids and fat-soluble micronutrients are solubilized in mixed micelles and absorbed in the small intestine. Based on an assumption that cholesterol and other fat-soluble molecules share a number of transport mechanisms and the fact that Niemann-Pick C1-like 1 (NPC1L1) is critical for intestinal cholesterol ab...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.107.043034

    authors： Narushima K,Takada T,Yamanashi Y,Suzuki H

    更新日期：2008-07-01 00:00:00

  • Multiple conformations of native and recombinant human 5-hydroxytryptamine(2a) receptors are labeled by agonists and discriminated by antagonists.

    abstract：:We have expanded previous studies with the 5-hydroxytryptamine (5-HT)(2) receptor agonist (+/-)-1-(2,5-dimethoxy-4-[(125)I]iodophenyl)-2-aminopropane [(+/-)-[(125)I]DOI] in human brain that had shown biphasic competition curves for several 5-HT(2A) receptor antagonists by using new selective antagonists of 5-HT(2A) (M...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： López-Giménez JF,Villazón M,Brea J,Loza MI,Palacios JM,Mengod G,Vilaró MT

    更新日期：2001-10-01 00:00:00

  • Muscarinic receptors in canine colonic circular smooth muscle. II. Signal transduction pathways.

    abstract：:We have, in the accompanying work, demonstrated the coexistence of M2 and M3 muscarinic receptors in the circular smooth muscle of canine colon. In the present study, the effects of muscarinic receptor stimulation on phosphoinositide turnover and adenylate cyclase activity were examined. In myo-[3H]inositol-labeled ci...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Zhang LB,Buxton IL

    更新日期：1991-12-01 00:00:00

  • Efficient binding of 4/7 α-conotoxins to nicotinic α4β2 receptors is prevented by Arg185 and Pro195 in the α4 subunit.

    abstract：:α-Conotoxins are subtype-selective nicotinic acetylcholine receptor (nAChR) antagonists. Although potent α3β2 nAChR-selective α-conotoxins have been identified, currently characterized α-conotoxins show no or only weak affinity for α4β2 nAChRs, which are, besides α7 receptors, the most abundant nAChRs in the mammalian...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.112.078683

    authors： Beissner M,Dutertre S,Schemm R,Danker T,Sporning A,Grubmüller H,Nicke A

    更新日期：2012-10-01 00:00:00

  • Immortalized hypothalamic GT1-7 neurons express functional gamma-aminobutyric acid type A receptors.

    abstract：:Neuronal cell lines provide a source of pure populations of neurons and allow the properties of many neurotransmitter receptors to be studied. However, none of these cells have been reported to express functional gamma-aminobutyric acid (GABA)A receptors. Indeed, there have been no reports of cell lines expressing fun...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Hales TG,Kim H,Longoni B,Olsen RW,Tobin AJ

    更新日期：1992-08-01 00:00:00

  • Differential activation of human gastrin-releasing peptide receptor-mediated responses by bombesin analogs.

    abstract：:To enable the detailed pharmacological characterization of five bombesin (BN) analogs with respect to the human gastrin-releasing peptide (GRP) receptor, we ectopically expressed the receptor in BALB/3T3 cells. In such cells (termed GR1 cells), GRP stimulated DNA synthesis and Ca2+ mobilization. Two of these analogs, ...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Wu JM,Hoang DO,Feldman RI

    更新日期：1995-04-01 00:00:00

  • Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells.

    abstract：:Gemcitabine and pemetrexed are effective agents in the treatment of non-small-cell lung cancer (NSCLC), and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1, and Calu-6 cells. Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed usi...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.104.009373

    authors： Giovannetti E,Mey V,Nannizzi S,Pasqualetti G,Marini L,Del Tacca M,Danesi R

    更新日期：2005-07-01 00:00:00

  • Nuclear xenobiotic receptor pregnane X receptor locks corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) onto the CYP24A1 promoter to attenuate vitamin D3 activation.

    abstract：:We have studied the molecular mechanism by which the nuclear xenobiotic receptors pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR) regulate transcription of the vitamin D(3) 24-hydroxylase (CYP24A1) gene. In the absence of vitamin D(3), PXR activates the CYP24A1 gene by directly binding to a...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.108.051904

    authors： Konno Y,Kodama S,Moore R,Kamiya N,Negishi M

    更新日期：2009-02-01 00:00:00

  • Nootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons.

    abstract：:Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia. Because the cholinergic system plays an important role in cognitive functions and Alzheimer's disease dementia, the present study was conducted to elucidate the mechani...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.59.4.674

    authors： Zhao X,Kuryatov A,Lindstrom JM,Yeh JZ,Narahashi T

    更新日期：2001-04-01 00:00:00

  • Identification and characterization of PDE4A11, a novel, widely expressed long isoform encoded by the human PDE4A cAMP phosphodiesterase gene.

    abstract：:PDE4A11 is a novel cAMP-specific phosphodiesterase that is conserved in humans, mouse, rat, pig, and bat. Exon-1(4A11) encodes its unique, 81 amino acid N-terminal region. Reverse-transcriptase polymerase chain reaction performed across the splice junction, plus identification of expressed sequence tags, identifies PD...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.104.009423

    authors： Wallace DA,Johnston LA,Huston E,MacMaster D,Houslay TM,Cheung YF,Campbell L,Millen JE,Smith RA,Gall I,Knowles RG,Sullivan M,Houslay MD

    更新日期：2005-06-01 00:00:00

  • Molecular Pharmacology of Class F Receptor Activation.

    abstract：:The class Frizzled (FZD) or class F of G protein-coupled receptors consists of 10 FZD paralogues and Smoothened (SMO). FZDs coordinate wingless/Int-1 signaling and SMO mediates Hedgehog signaling. Class F receptor signaling is intrinsically important for embryonic development and its dysregulation leads to diseases, i...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章,评审

    doi：10.1124/mol.119.117986

    authors： Kozielewicz P,Turku A,Schulte G

    更新日期：2020-02-01 00:00:00

  • Effect of avermectin B1a on chick neuronal gamma-aminobutyrate receptor channels expressed in Xenopus oocytes.

    abstract：:Chick brain mRNA was isolated and injected into Xenopus oocytes. This led to the expression of gamma-aminobutyrate (GABA) channels easily accessible for current measurements using the voltage clamp technique. The effect of the anthelmintic natural product avermectin B1a on the GABA current was studied quantitatively. ...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Sigel E,Baur R

    更新日期：1987-12-01 00:00:00

  • Evidence for a new G protein-coupled cannabinoid receptor in mouse brain.

    abstract：:The purpose of these studies was to support the hypothesis that an undiscovered cannabinoid receptor exists in brain. [(35)S]GTP gamma S binding was stimulated by anandamide and WIN55212-2 in brain membranes from both CB(1)(+/+) and CB(1)(-/-) mice. In contrast, a wide variety of other compounds that are known to acti...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Breivogel CS,Griffin G,Di Marzo V,Martin BR

    更新日期：2001-07-01 00:00:00

  • 2,3,7,8-tetrachlorodibenzo-p-dioxin increases cardiac myocyte intracellular calcium and progressively impairs ventricular contractile responses to isoproterenol and to calcium in chick embryo hearts.

    abstract：:Binding by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor leads to transcriptional activation of several genes and a toxicity syndrome that includes tumor promotion, wasting, hormonal and immune system dysfunction, and death. Recent findings indicate that TCDD may also affect cardiac function. Here, we ...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Canga L,Paroli L,Blanck TJ,Silver RB,Rifkind AB

    更新日期：1993-12-01 00:00:00

  • Selective and synergistic inhibition of human immunodeficiency virus type 1 reverse transcriptase by a non-nucleoside inhibitor, MKC-442.

    abstract：:In the search for 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives, we have found 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil (MKC-442) to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). The IC50 value of MKC-442 for HIV-1 RT was 8 nM....

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Yuasa S,Sadakata Y,Takashima H,Sekiya K,Inouye N,Ubasawa M,Baba M

    更新日期：1993-10-01 00:00:00

  • Structural basis for ether-a-go-go-related gene K+ channel subtype-dependent activation by niflumic acid.

    abstract：:Niflumic acid [2-((3-(trifluoromethyl)phenyl)amino)-3-pyridinecarboxylic acid, NFA] is a nonsteroidal anti-inflammatory drug that also blocks or modulates the gating of a wide spectrum of ion channels. Here we investigated the mechanism of channel activation by NFA on ether-a-go-go-related gene (ERG) K(+) channel subt...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.107.043505

    authors： Fernandez D,Sargent J,Sachse FB,Sanguinetti MC

    更新日期：2008-04-01 00:00:00

  • Effects of active and inactive phospholipase D2 on signal transduction, adhesion, migration, invasion, and metastasis in EL4 lymphoma cells.

    abstract：:The phosphatidylcholine-using phospholipase D (PLD) isoform PLD2 is widely expressed in mammalian cells and is activated in response to a variety of promitogenic agonists. In this study, active and inactive hemagglutinin-tagged human PLD2 (HA-PLD2) constructs were stably expressed in an EL4 cell line lacking detectabl...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.107.040105

    authors： Knoepp SM,Chahal MS,Xie Y,Zhang Z,Brauner DJ,Hallman MA,Robinson SA,Han S,Imai M,Tomlinson S,Meier KE

    更新日期：2008-09-01 00:00:00

  • Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.

    abstract：:Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)eth...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.115.099747

    authors： Huang M,Shao Y,Hou J,Cui W,Liang B,Huang Y,Li Z,Wu Y,Zhu X,Liu P,Wan Y,Ke H,Luo HB

    更新日期：2015-11-01 00:00:00

  • Aspirin-mediated COX-2 transcript stabilization via sustained p38 activation in human intestinal myofibroblasts.

    abstract：:Acetylsalicylic acid (aspirin) is a cyclooxygenase (COX) inhibitor, yet some of its therapeutic effects are thought to derive from mechanisms unrelated to prostaglandin synthesis inhibition. In human intestinal myofibroblasts, aspirin, at therapeutic doses, had the unexpected effect of inducing prolonged COX-2 express...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.65.2.470

    authors： Mifflin RC,Saada JI,Di Mari JF,Valentich JD,Adegboyega PA,Powell DW

    更新日期：2004-02-01 00:00:00

  • Interpretation of binding curves obtained with high receptor concentrations: practical aid for computer analysis.

    abstract：:Typical equilibrium binding experiments cannot be quantitatively analyzed on the basis of classical mathematical equations when the receptor concentration is so high that a significant fraction of the added radioligand concentration is in the bound form. In this paper, the appropriate equations are derived and used in...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Swillens S

    更新日期：1995-06-01 00:00:00

  • Copper-dependent oxidative and topoisomerase II-mediated DNA cleavage by a netropsin/4'-(9-acridinylamino)methanesulfon-m-anisidide combilexin.

    abstract：:A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4'-(9-acridinylamino)methanesulfon-manisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/ mAMSA) behaves as a ...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：

    authors： Henichart JP,Waring MJ,Riou JF,Denny WA,Bailly C

    更新日期：1997-03-01 00:00:00

  • GRK2 Mediates Arginine Vasopressin-Induced Interleukin-6 Production via Nuclear Factor-κB Signaling Neonatal Rat Cardiac Fibroblast.

    abstract：:Interleukin 6 (IL-6), which is elevated in patients with congestive heart failure and acts as both a chronic marker of inflammation and an acute-phase reactant, is associated with myocardial damage. Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and could be a factor for cardiac in...

    journal_title：Molecular pharmacology

    pub_type： 杂志文章

    doi：10.1124/mol.116.107698

    authors： Xu F,Sun S,Wang X,Ni E,Zhao L,Zhu W

    更新日期：2017-09-01 00:00:00