The human histamine H1 G-protein coupled receptor (GPCR) is an important drug target for immunological disorders. A homology model of the human H1 GPCR was developed based on the crystal structure of the human �2 adrenoceptor (�2AR). Ligand docking studies and molecular dynamics (MD) simulations at the human H1 receptor model were undertaken and validated by experimental results from binding studies using wild type as well as novel (Y3.33A, W4.56A, F5.47A, W6.48A, Y6.51A), and known (D3.32A, F6.52A, F6.55A, Y7.43A) point-mutated human H1 receptors. Differences in ligand binding modes at the human H1 model correlated to differences in ligand binding affinities at the human H1 receptor. The �2AR-based human H1 homology model was compared to the recently reported crystal structure of the human H1 receptor at 3.1 � resolution (PDB code 3RZE): superposition of alpha-carbons in transmembrane domains of the human H1 model with 3RZE gave RMSD = 2.91 �, indicating the �2AR structure is an accurate template for human H1 GPCR homology modeling.

Human H1 receptor studies: Homology model validation, docking and mutagenesis

243rd National Meeting (2012)

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