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Crystal Structure-Based Virtual Screening for Fragment-like Ligands of the Human Histamine H1 Receptor

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Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Faculty of Science, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, GAC-1200, La Jolla, California 92037, United States
§ Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Division of Molecular Biosciences, Membrane Protein Crystallography Group, Imperial College, London SW7 2AZ, U.K.
# Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot, Oxfordshire OX11 0DE, U.K.
× Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-Ku, Kyoto 606-8501, Japan
Phone: +31 20 5987600. Fax: +31 20 5987610. E-mail: [email protected]
Cite this: J. Med. Chem. 2011, 54, 23, 8195–8206
Publication Date (Web):October 18, 2011
Copyright © 2011 American Chemical Society

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    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 H1 receptor (H1R) 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) H1R 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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    Additional analysis results of the retrospective and prospective virtual screening studies, H1R, H3R, and H4R radioligand displacement curves, and InsP accumulation barplots; a zipped file containing molecular structures of ligand test set (SMILES) and receptor mol2 coordinates (H1R crystal structure), PLANTS docking conf(iguration) file, reference IFP bit-strings, and cavity coordinates used for IFP calculations. This material is available free of charge via the Internet at

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