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In silico analysis of the histaprodifen induced activation pathway of the guinea-pig histamine H1-receptor

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Abstract

The binding of (partial) agonists in the binding pocket of biogenic amine receptors induces a conformational change from the inactive to the active state of the receptors. There is only little knowledge about the binding pathways of ligands into binding pocket on molecular level. So far, it was not possible with molecular dynamic simulations to observe the ligand binding and receptor activation. Furthermore, there is nearly nothing known, in which state of ligand binding, the receptor gets activated. The aim of this study was to get more detailed insight into the process of ligand binding and receptor activation. With the recently developed LigPath algorithm, we scanned the potential energy surface of the binding process of dimeric histaprodifen, a partial agonist at the histamine H1-receptor, into the guinea pig histamine H1-receptor, taking also into account the receptor activation. The calculations exhibited large conformational changes of Trp6.48 and Phe6.55 during ligand binding and receptor activation. Additionally, conformational changes were also observed for Phe6.52, Tyr6.51 and Phe6.44. Conformational changes of Trp6.48 and Phe6.52 are discussed in literature as rotamer toggle switch in context with receptor activation. Additionally, the calculations indicate that the binding of dimeric histaprodifen, accompanied by receptor activation is energetically preferred. In general, this study gives new, theoretical insights onto ligand binding and receptor activation on molecular level.

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Acknowledgments

We thank the DFG (Deutsche Forschungsgemeinschaft) for further support of this project.

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Authors and Affiliations

  1. Department of Pharmaceutical and Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany

    Andrea Straßer

  2. Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany

    Hans-Joachim Wittmann

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  1. Andrea Straßer
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  2. Hans-Joachim Wittmann
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Correspondence to Andrea Straßer.

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Straßer, A., Wittmann, HJ. In silico analysis of the histaprodifen induced activation pathway of the guinea-pig histamine H1-receptor. J Comput Aided Mol Des 24, 759–769 (2010). https://doi.org/10.1007/s10822-010-9372-2

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  • DOI: https://doi.org/10.1007/s10822-010-9372-2

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