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

doi:10.1021/jm2011589

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^*

^*Corresponding author for this work

173 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 language	English
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	23
Pages (from-to)	8195-8206
Number of pages	12
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm2011589
Publication status	Published - 8 Dec 2011
Externally published	Yes

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

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.",

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T1 - Crystal structure-based virtual screening for fragment-like ligands of the human histamine H 1 receptor

AU - De Graaf, Chris

AU - Kooistra, Albert J.

AU - Vischer, Henry F.

AU - Katritch, Vsevolod

AU - Kuijer, Martien

AU - Shiroishi, Mitsunori

AU - Iwata, So

AU - Shimamura, Tatsuro

AU - Stevens, Raymond C.

AU - De Esch, Iwan J P

AU - Leurs, Rob

PY - 2011/12/8

Y1 - 2011/12/8

N2 - 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.

AB - 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.

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

Abstract

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