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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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
JournalJournal of Medicinal Chemistry
Issue number23
Pages (from-to)8195-8206
Number of pages12
Publication statusPublished - 8 Dec 2011
Externally publishedYes

ID: 199377144