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.
Due to its overexpression and activation in human cancer cells and tissues, an emerging molecular target in cancer therapeutics is p90 ribosomal s6 kinase 2 (RSK2). While a growing number of RSK2 inhibitors have been reported in the literature, only the crystal structure of RSK2 in complex with an AMP analogue provides a structural basis for understanding RSK2 inhibition. To remedy this, we used our fluorescence polarization assay to determine the RSK2 activity for a set of structurally diverse compounds, and followed this by modeling their binding modes in an all-atom, energy refined crystal structure of RSK2. These binding models reveal that Val131 and Leu147 are key interaction sites for potent RSK2 inhibition. This structure-based pharmacophore is an important tool for new lead discovery and refinement.
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