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      Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation

      research-article
      Author(s): a , * , a , b , c , c , a , b , b , c , a , d
      Publication date PMC-release:
      Journal: Bioorganic & Medicinal Chemistry
      Publisher: Elsevier Science
      Keywords: 6-ECDCA, 6-ethylchenodeoxycholic acid, AF, activation function, BSEP, bile salt export pump, CA, cholic acid, CDCA, chenodeoxycholic acid, DCA, deoxycholic acid, DMEM, Dulbecco’s Modified Eagle’s Medium, EF, enrichment factor, FBS, fetal bovine serum, FXR, farnesoid X receptor, H-bond, hydrogen bond, HEK-293, human embryonic kidney-293, IBABP, intestinal bile acid-binding protein, LCA, lithocholic acid, LRH-1, liver receptor homolog 1, LXR, liver X receptor, NCI, National Cancer Institute, PDB, Protein Data Bank, RXR, 9-cis-retionic acid receptor, SD file, structure-data file, SHP-1, small heterodimer partner 1, WDI, World Drug Index, Farnesoid X receptor, Molecular modeling, Virtual screening, Lead identification, FXR agonist

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          Abstract

          The farnesoid X receptor (FXR) is involved in glucose and lipid metabolism regulation, which makes it an attractive target for the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. In order to find novel FXR agonists, a structure-based pharmacophore model collection was developed and theoretically evaluated against virtual databases including the ChEMBL database. The most suitable models were used to screen the National Cancer Institute (NCI) database. Biological evaluation of virtual hits led to the discovery of a novel FXR agonist with a piperazine scaffold (compound 19) that shows comparable activity as the endogenous FXR agonist chenodeoxycholic acid (CDCA, compound 2).

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          Improved protein-ligand docking using GOLD.

          Marcel Verdonk, Jason Cole, Michael J Hartshorn … (2003)
          The Chemscore function was implemented as a scoring function for the protein-ligand docking program GOLD, and its performance compared to the original Goldscore function and two consensus docking protocols, "Goldscore-CS" and "Chemscore-GS," in terms of docking accuracy, prediction of binding affinities, and speed. In the "Goldscore-CS" protocol, dockings produced with the Goldscore function are scored and ranked with the Chemscore function; in the "Chemscore-GS" protocol, dockings produced with the Chemscore function are scored and ranked with the Goldscore function. Comparisons were made for a "clean" set of 224 protein-ligand complexes, and for two subsets of this set, one for which the ligands are "drug-like," the other for which they are "fragment-like." For "drug-like" and "fragment-like" ligands, the docking accuracies obtained with Chemscore and Goldscore functions are similar. For larger ligands, Goldscore gives superior results. Docking with the Chemscore function is up to three times faster than docking with the Goldscore function. Both combined docking protocols give significant improvements in docking accuracy over the use of the Goldscore or Chemscore function alone. "Goldscore-CS" gives success rates of up to 81% (top-ranked GOLD solution within 2.0 A of the experimental binding mode) for the "clean list," but at the cost of long search times. For most virtual screening applications, "Chemscore-GS" seems optimal; search settings that give docking speeds of around 0.25-1.3 min/compound have success rates of about 78% for "drug-like" compounds and 85% for "fragment-like" compounds. In terms of producing binding energy estimates, the Goldscore function appears to perform better than the Chemscore function and the two consensus protocols, particularly for faster search settings. Even at docking speeds of around 1-2 min/compound, the Goldscore function predicts binding energies with a standard deviation of approximately 10.5 kJ/mol. Copyright 2003 Wiley-Liss, Inc.
          Article 0 comments Cited 604 times – based on 0 reviews     Review now
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            A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

            Bryan Goodwin, Stacey A. Jones, Roger Price … (2000)
            Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
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              6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity.

              Roberto Pellicciari, Stefano Fiorucci, Emidio Camaioni … (2002)
              A series of 6alpha-alkyl-substituted analogues of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist (EC(50) = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.
              Article 0 comments Cited 106 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Bioorg Med Chem
                Journal ID (iso-abbrev): Bioorg. Med. Chem
                Title: Bioorganic & Medicinal Chemistry
                Publisher: Elsevier Science
                ISSN (Print): 0968-0896
                ISSN (Electronic): 1464-3391
                Publication date PMC-release: 01 December 2011
                Publication date (Print): 01 December 2011
                Volume: 19
                Issue: 23
                Pages: 7168-7180
                Affiliations
                [a ]Computer-Aided Molecular Design Group, Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Molecular Biosciences Innsbruck – CMBI, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria
                [b ]Institute of Pharmacy, Department of Pharmacognosy, Center for Molecular Biosciences Innsbruck – CMBI, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria
                [c ]Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, Austria
                [d ]Institute of Pharmacy, Department of Pharmaceutical Chemistry, Freie University Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany
                Author notes
                [* ]Corresponding author. Tel.: +43 512 507 5253; fax: +43 512 507 5269. Daniela.Schuster@ 123456uibk.ac.at
                Article
                Publisher ID: BMC9540
                DOI: 10.1016/j.bmc.2011.09.056
                PMC ID: 3254253
                PubMed ID: 22018919
                SO-VID: 4cf1d3c5-4c63-404c-a373-1bc83c239bcb
                Copyright © © 2011 Elsevier Ltd.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 17 June 2011
                Date revision received : 26 September 2011
                Date accepted : 28 September 2011
                Categories
                Subject: Article

                ScienceOpen disciplines: Pharmaceutical chemistry
                Keywords: af, activation function,shp-1, small heterodimer partner 1,h-bond, hydrogen bond,dmem, dulbecco’s modified eagle’s medium,sd file, structure-data file,fxr, farnesoid x receptor,lead identification,hek-293, human embryonic kidney-293,ef, enrichment factor,fxr agonist,ca, cholic acid,lca, lithocholic acid,6-ecdca, 6-ethylchenodeoxycholic acid,fbs, fetal bovine serum,rxr, 9-cis-retionic acid receptor,pdb, protein data bank,lrh-1, liver receptor homolog 1,virtual screening,ibabp, intestinal bile acid-binding protein,lxr, liver x receptor,dca, deoxycholic acid,molecular modeling,farnesoid x receptor,bsep, bile salt export pump,wdi, world drug index,nci, national cancer institute,cdca, chenodeoxycholic acid
                Data availability:
                ScienceOpen disciplines: Pharmaceutical chemistry
                Keywords: af, activation function, shp-1, small heterodimer partner 1, h-bond, hydrogen bond, dmem, dulbecco’s modified eagle’s medium, sd file, structure-data file, fxr, farnesoid x receptor, lead identification, hek-293, human embryonic kidney-293, ef, enrichment factor, fxr agonist, ca, cholic acid, lca, lithocholic acid, 6-ecdca, 6-ethylchenodeoxycholic acid, fbs, fetal bovine serum, rxr, 9-cis-retionic acid receptor, pdb, protein data bank, lrh-1, liver receptor homolog 1, virtual screening, ibabp, intestinal bile acid-binding protein, lxr, liver x receptor, dca, deoxycholic acid, molecular modeling, farnesoid x receptor, bsep, bile salt export pump, wdi, world drug index, nci, national cancer institute, cdca, chenodeoxycholic acid

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