title: Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies.
abstract: The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.
authors: Department of Pharmacochemistry, Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors: Enade P
authors: EP
authors: Istyastono
authors: Saskia
authors: S
authors: Nijmeijer
authors: Herman D
authors: HD
authors: Lim
authors: Andrea
authors: A
authors: van de Stolpe
authors: Luc
authors: L
authors: Roumen
authors: Albert J
authors: AJ
authors: Kooistra
authors: Henry F
authors: HF
authors: Vischer
authors: Iwan J P
authors: IJ
authors: de Esch
authors: Rob
authors: R
authors: Leurs
authors: Chris
authors: C
authors: de Graaf
mesh_terms: D045744:Cell Line, Tumor; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013237:Stereoisomerism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C418607:HRH4 protein, human; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D013890:Thiourea; C086108:clobenpropit