title: In silico analysis of the histaprodifen induced activation pathway of the guinea-pig histamine H(1)-receptor.
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 H(1)-receptor, into the guinea pig histamine H(1)-receptor, taking also into account the receptor activation. The calculations exhibited large conformational changes of Trp(6.48) and Phe(6.55) during ligand binding and receptor activation. Additionally, conformational changes were also observed for Phe(6.52), Tyr(6.51) and Phe(6.44). Conformational changes of Trp(6.48) and Phe(6.52) 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.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany. andrea.strasser@chemie.uni-regensburg.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Strasser
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wittmann
mesh_terms: D000465:Algorithms; D000818:Animals; D006168:Guinea Pigs; D006632:Histamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D012984:Software
chemical_list: D011969:Receptors, Histamine H1; C118994:histaprodifen; D006632:Histamine