title: A new crystal structure fragment-based pharmacophore method for G protein-coupled receptors.
abstract: We have developed a new method for the building of pharmacophores for G protein-coupled receptors, a major drug target family. The method is a combination of the ligand- and target-based pharmacophore methods and founded on the extraction of structural fragments, interacting ligand moiety and receptor residue pairs, from crystal structure complexes. We describe the procedure to collect a library with more than 250 fragments covering 29 residue positions within the generic transmembrane binding pocket. We describe how the library fragments are recombined and inferred to build pharmacophores for new targets. A validating retrospective virtual screening of histamine H1 and H3 receptor pharmacophores yielded area-under-the-curves of 0.88 and 0.82, respectively. The fragment-based method has the unique advantage that it can be applied to targets for which no (homologous) crystal structures or ligands are known. 47% of the class A G protein-coupled receptors can be targeted with at least four-element pharmacophores. The fragment libraries can also be used to grow known ligands or for rotamer refinement of homology models. Researchers can download the complete fragment library or a subset matching their receptor of interest using our new tool in GPCRDB.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: kimberleyfidom@gmail.com.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Fidom
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: vis@sund.ku.dk.
authors.forename: Vignir
authors.initials: V
authors.lastname: Isberg
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: alexshauser@gmail.com.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Hauser
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Electronic address: stefanm@if-pan.krakow.pl.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mordalski
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: thomas@leh2.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lehto
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Poland. Electronic address: bojarski@if-pan.krakow.pl.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: david.gloriam@sund.ku.dk.
authors.forename: David E
authors.initials: DE
authors.lastname: Gloriam
mesh_terms: D018360:Crystallography, X-Ray / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled
keywords: Drug discovery; Fragment-based drug design; G protein-coupled receptor; Pharmacophore; Virtual screening