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

Update 1 of: Computational Modeling Approaches to Structure–Function Analysis of G Protein-Coupled Receptors

“…795 The LigPath algorithm was recently used to scan the potential energy surface of the binding process of dimeric histaprodifen, a partial agonist at H 1 R, to a H 1 R model based upon the crystal structure of rhodopsin. 796 The difficulties in simulating the ligand entry into the receptor binding site are also linked to indetermination in the arrangements of the extracellular loops, which are expected to play a relevant role in ligand recognition. Before the release of the crystal structures of nonopsin GPCRs, the extracellular domains were predicted to form a tightly bound canopy that makes ligand entry difficult.…”

“…Microsecond MD simulations in explicit membrane/water led to hypothesize that a classical cannabinoid would enter through a lipid pathway involving the TM interface between H6 and H7 . The LigPath algorithm was recently used to scan the potential energy surface of the binding process of dimeric histaprodifen, a partial agonist at H 1 R, to a H 1 R model based upon the crystal structure of rhodopsin . The difficulties in simulating the ligand entry into the receptor binding site are also linked to indetermination in the arrangements of the extracellular loops, which are expected to play a relevant role in ligand recognition.…”

Modelling of GPCRs

“…In the intracellular part, GPCRs, activated by the binding of an agonist, are able to interact with heterotrimeric G proteins, consisting of a α-, βand γ -subunit ( Fig. In order to get a more detailed insight into interactions between a GPCR and the Gα-subunit, in 2010, a hβ 2 R-Gα s -complex was predicted (Strasser et al 2010). There is only small knowledge about the interaction between GPCR and G protein on molecular level available.…”