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J Med Chem. 2011 Dec 8;54(23):8195-206. doi: 10.1021/jm2011589. Epub 2011 Nov 7.

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

Author information

1
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

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(1)R) 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(1)R 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.

PMID:
22007643
PMCID:
PMC3228891
DOI:
10.1021/jm2011589
[Indexed for MEDLINE]
Free PMC Article

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