Crystal structure-based virtual screening for fragment-like ligands of the human histamine H 1 receptor

Chris De Graaf, Albert J. Kooistra, Henry F. Vischer, Vsevolod Katritch, Martien Kuijer, Mitsunori Shiroishi, So Iwata, Tatsuro Shimamura, Raymond C. Stevens, Iwan J.P. De Esch, Rob Leurs

Research output: Contribution to journalArticlepeer-review

168 Citations (Scopus)

Abstract

The recent crystal structure determinations of druggable class A G protein-coupled receptors (GPCRs) have opened up excellent opportunities in structure-based ligand discovery for this pharmaceutically important protein family. We have developed and validated a customized structure-based virtual fragment screening protocol against the recently determined human histamine H 1 receptor (H 1R) crystal structure. The method combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. The optimized in silico screening approach was successfully applied to identify a chemically diverse set of novel fragment-like (≥22 heavy atoms) H 1R ligands with an exceptionally high hit rate of 73%. Of the 26 tested fragments, 19 compounds had affinities ranging from 10 μM to 6 nM. The current study shows the potential of in silico screening against GPCR crystal structures to explore novel, fragment-like GPCR ligand space.

Original languageEnglish
Pages (from-to)8195-8206
Number of pages12
JournalJournal of Medicinal Chemistry
Volume54
Issue number23
DOIs
Publication statusPublished - Dec 8 2011

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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