Molecular determinants of ligand binding at the human histamine H1 receptor: Site-directed mutagenesis results analyzed with ligand docking and molecular dynamics studies at H1 homology and crystal structure models.

The human histamine H1 G-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 H1 receptor models were built by homology to the crystal structure of the human β2 adrenoceptor (β2AR) and from the recently reported crystal structure of the human H1 receptor complex with doxepin at 3.1 Å (PDB code 3RZE). Ligand affinity of histamine and the H1 antagonists 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 H1 receptors were determined experimentally and results analyzed by ligand docking and molecular dynamic studies at WT and point-mutated H1 receptor 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 H1 drug design.