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

TY - JOUR

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.

UR - http://www.scopus.com/inward/record.url?scp=82555187387&partnerID=8YFLogxK

U2 - 10.1021/jm2011589

DO - 10.1021/jm2011589

M3 - Journal article

C2 - 22007643

AN - SCOPUS:82555187387

SN - 0022-2623

VL - 54

SP - 8195

EP - 8206

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -