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(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.
authors: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors: Chris
authors: C
authors: de Graaf
authors: Albert J
authors: AJ
authors: Kooistra
authors: Henry F
authors: HF
authors: Vischer
authors: Vsevolod
authors: V
authors: Katritch
authors: Martien
authors: M
authors: Kuijer
authors: Mitsunori
authors: M
authors: Shiroishi
authors: So
authors: S
authors: Iwata
authors: Tatsuro
authors: T
authors: Shimamura
authors: Raymond C
authors: RC
authors: Stevens
authors: Iwan J P
authors: IJ
authors: de Esch
authors: Rob
authors: R
authors: Leurs
mesh_terms: D016208:Databases, Factual; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D011969:Receptors, Histamine H1