Prev. Article Next Article Table of Contents

Article

Discovery of Novel Human Histamine H4 Receptor Ligands by Large-Scale Structure-Based Virtual Screening

Supporting Info

Róbert Kiss^†^‡, Béla Kiss^†, Árpád Könczöl^†, Ferenc Szalai^§, Ivett Jelinek, Valéria László, Béla Noszál^‡, András Falus and György M. Keser

*^†

Gedeon Richter Plc, Gyömr

i út 19-21, H-1103, Budapest, Hungary, Department of Pharmaceutical Chemistry, Semmelweis University, H

gyes Endre u. 9, H-1092, Budapest, Hungary, National Information Infrastructure Institute, Victor Hugo u. 18-22, H-1132, Budapest, Hungary, Department of Genetics, Cell Biology, and Immunobiology, Semmelweis University, Nagyvárad tér 4, H-1089, Budapest, Hungary, Department of General and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért tér 4, H-1111, Budapest, Hungary

J. Med. Chem., 2008, 51 (11), pp 3145–3153

DOI: 10.1021/jm7014777

Publication Date (Web): May 7, 2008

†

Gedeon Richter Plc.

‡

Department of Pharmaceutical Chemistry, Semmelweis University.

National Information Infrastructure Institute.

Department of Genetics, Cell Biology, and Immunobiology, Semmelweis University.

* To whom correspondence should be addressed. Phone: +36-1-4314605 . Fax: +36-1-4326002. E-mail: gy.keseru@richter.hu.

Budapest University of Technology and Economics.

Abstract

A structure-based virtual screening (SBVS) was conducted on a ligand-supported homology model of the human histamine H4 receptor (hH4R). More than 8.7 million 3D structures derived from different vendor databases were investigated by docking to the hH4R binding site using FlexX. A total of 255 selected compounds were tested by radioligand binding assay and 16 of them possessed significant [³H]histamine displacement. Several novel scaffolds were identified that can be used to develop selective H4 ligands in the future. As far as we know, this is the first SBVS reported on H4R, representing one of the largest virtual screens validated by the biological evaluation of the virtual hits.

View: Full Text HTML | Hi-Res PDF | PDF w/ Links

Tools

SciFinder Links

History

Published In Issue June 12, 2008
Article ASAPMay 07, 2008
Received: November 27, 2007

Recommend & Share

Related Content

Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H₄ Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation ModelsJournal of Medicinal Chemistry
- Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H₄ Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models
  Marlon D. Cowart, Robert J. Altenbach, Huaqing Liu, Gin C. Hsieh, Irene Drizin, Ivan Milicic, Thomas R. Miller, David G. Witte, Neil Wishart, Shannon R. Fix-Stenzel, Michael J. McPherson, Ronald M. Adair, Jill M. Wetter, Brian M. Bettencourt, Kennan C. Marsh, James P. Sullivan, Prisca Honore, Timothy A. Esbenshade and Jorge D. Brioni
  Journal of Medicinal Chemistry 2008 51 (20), pp 6547–6557
  Abstract: A new structural class of histamine H₄ receptor antagonists (6−14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H₄ antagonism across multiple species, good CNS penetration, ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF
Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H₄ Receptor LigandsJournal of Medicinal Chemistry
- Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H₄ Receptor Ligands
  Robert J. Altenbach, Ronald M. Adair, Brian M. Bettencourt, Lawrence A. Black, Shannon R. Fix-Stenzel, Sujatha M. Gopalakrishnan, Gin C. Hsieh, Huaqing Liu, Kennan C. Marsh, Michael J. McPherson, Ivan Milicic, Thomas R. Miller, Timothy A. Vortherms, Usha Warrior, Jill M. Wetter, Neil Wishart, David G. Witte, Prisca Honore, Timothy A. Esbenshade, Arthur A. Hancock, Jorge D. Brioni and Marlon D. Cowart
  Journal of Medicinal Chemistry 2008 51 (20), pp 6571–6580
  Abstract: A series of 2-aminopyrimidines was synthesized as ligands of the histamine H₄ receptor (H₄R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4-...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF
cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), A New Histamine H₄R Antagonist that Blocks Pain Responses against Carrageenan-Induced HyperalgesiaJournal of Medicinal Chemistry
- cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), A New Histamine H₄R Antagonist that Blocks Pain Responses against Carrageenan-Induced Hyperalgesia
  Huaqing Liu, Robert J. Altenbach, Tracy L. Carr, Prasant Chandran, Gin C. Hsieh, La Geisha R. Lewis, Arlene M. Manelli, Ivan Milicic, Kennan C. Marsh, Thomas R. Miller, Marina I. Strakhova, Timothy A. Vortherms, Brian D. Wakefield, Jill M. Wetter, David G. Witte, Prisca Honore, Timothy A. Esbenshade, Jorge D. Brioni and Marlon D. Cowart
  Journal of Medicinal Chemistry 2008 51 (22), pp 7094–7098
  Abstract: cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H₄ antagonist. The compound is potent in H₄ receptor binding assays (rat H₄, K_i = 3.4 nM, human H₄K_i = 5.8 nM) and demonstrated ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF

Article

Discovery of Novel Human Histamine H4 Receptor Ligands by Large-Scale Structure-Based Virtual Screening