title: Molecular determinants of ligand binding at the human histamine H1receptor: Site-directed mutagenesis results analyzed with ligand docking and molecular dynamics studies at H1homology and crystal structure models.
abstract: The human histamine H1G-protein coupled receptor (GPCR) is an important drug target for inflammatory, sleep, and other neuropsychiatric disorders. To delineate molecular determinants for ligand binding for drug discovery purposes, human H1receptor models were built by homology to the crystal structure of the human β2adrenoceptor (β2AR) and from the recently reported crystal structure of the human H1receptor complex with doxepin at 3.1 Å (PDB code 3RZE). Ligand affinity of histamine and the H1antagonists mepyramine and (2S, 4R)-(-)-trans-4-phenyl-2-N, N-dimethylaminotetralin (PAT) at wild type and point-mutated (D3.32A, Y3.33A, W4.56A, F5.47A, W6.48A, Y6.51A, F6.52A, F6.55A, Y7.43A) human H1receptors were determined experimentally and results analyzed by ligand docking and molecular dynamic studies at WT and point-mutated H1receptor models. Differences in ligand binding affinities correlated to differences in ligand binding modes at models built according to homology or crystal structure, indicating, both models are accurate templates for predicting ligand affinity for H1drug design.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 US.
authors.forename: Tania C
authors.initials: TC
authors.lastname: Cordova-Sintjago
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 US.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, the Netherland.
authors.forename: Martijn
authors.initials: M
authors.lastname: Bruysters
authors.affiliation: Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, the Netherland.
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610 US ; Northeastern University Center for Drug Discovery, Boston, Massachusetts 02115, USA.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Booth
keywords: Human histamine H1 G protein-coupled receptor (GPCR); docking; homology modeling; molecular dynamics; site-directed mutagenesis