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Crystal Structure-Based Virtual Screening for Fragment-like Ligands of the Human Histamine H(1) Receptor

DOI: 10.1021/jm2011589 DOI Help

Authors: Chris De Graaf (VU University Amsterdam) , Albert J. Kooistra (VU University Amsterdam) , Henry F. Vischer (VU University Amsterdam) , Vsevolod Katritch (The Scripps Research Institute) , Martien Kuijer (VU University Amsterdam) , Mitsunori Shiroishi (Japan Science and Technology Agency; Kyushu University) , So Iwata (Japan Science and Technology Agency; Imperial College, London; Diamond Light Source; Kyoto University) , Tatsuro Shimamura (Japan Science and Technology Agency; Kyoto University) , Raymond C. Stevens (The Scripps Research Institute) , Iwan De Esch (VU University Amsterdam) , Rob Leurs (VU University Amsterdam)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 54 (23) , PAGES 8195-8206

State: Published (Approved)
Published: December 2011

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) Hilt. ligands with an exceptionally high hit rate of 73%. Of the 26 tested fragments, 19 compounds had affinities ranging from 10 mu M 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.

Subject Areas: Biology and Bio-materials

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Added On: 23/01/2012 14:23

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