title: Identification of Ligand Binding Hot Spots of the Histamine H1Receptor following Structure-Based Fragment Optimization.
abstract: Developments in G protein-coupled receptor (GPCR) structural biology provide insights into GPCR-ligand binding. Compound 1 (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1receptor (H1R) was used to design derivatives to investigate the roles of (i) the amine-binding region, (ii) the upper and lower aromatic region, and (iii) binding site solvation. SAR analysis showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water molecule from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of 1. Deconstruction of 1 showed that the lower aromatic region serves as a secondary binding hot spot. This study demonstrates that an X-ray structure in combination with tool compounds, assessment of water energetics, and mutagenesis studies enables SAR exploration to map GPCR-ligand binding hot spots.
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Kuhne
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kooistra
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Reggie
authors.initials: R
authors.lastname: Bosma
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Broadwater Road, Welwyn Garden City, Herts AL7 3AX, U.K.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bortolato
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Wijtmans
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.affiliation: Heptares Therapeutics Ltd. , BioPark, Broadwater Road, Welwyn Garden City, Herts AL7 3AX, U.K.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Mason
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011969:Receptors, Histamine H1 / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D008024:Ligands; D011969:Receptors, Histamine H1; D054852:Small Molecule Libraries