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Year: 2010  |  Volume: 9  |  Issue: 2  |  Page No.: 157 - 163

An in Silico Development of Selective Inhibitor for Histamine Receptors

Fakher Rahim    

Abstract: This study aimed to design a reliable homology model of human histamine H1 and H4 receptors (hH1R, hH4R), that would guide future biochemical and genetic efforts in its evaluation as a potential therapeutic target. Furthermore, these accurate models could aid in the structure-based inhibitor design for antagonists against the histamine H1 and H4 receptors. The homologous protein sequences of histamine receptors were retrieved from the NCBI REFSEQ which by using the sequence alignment program ClustalW alignment of the human histamine receptors sequence with Bovine Rhodopsin was conducted to locate the homology aligned regions. The present study found that Asp107 and Asn198 are in favorable positions for anchoring histamine. Identification of novel interaction sites for antagonist binding mutational data suggest a crucial role for Asp107, Trp158, Phe 432 and Phe 435 in antagonist binding. This study identified several novel amino acids at the binding site. Binding mode analysis of known H1 antagonists four known H1 antagonists (mepyramine, acrivastine, desloratadine, loratadine) were docked successfully to the binding site of the hH1R model by FlexiDock. The ligand used for optimizing the receptor model, the pharmacophore constraints and the different scoring functions applied in high throughput docking had all significant effect on the results. This research identified 16 compounds with 7 significant H4 activities representing an overall hit rate of 5.2%. To the best of our knowledge, this is one of the largest structure-based virtual screenings, where the virtual hits were confirmed by an in vitro assay. Moreover, this is the first structure-based drug design study reported on the hH4R. After the virtual screening, we identified several novel ligands with significant H4 affinity. These scaffolds can serve as starting points in the development of potent and selective H4 ligands in future.

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