Triazole Ligands Reveal Distinct Molecular Features That Induce Histamine H₄ Receptor Affinity and Subtly Govern H₄/H₃ Subtype Selectivity

Abstract

The histamine H(3) (H(3)R) and H(4) (H(4)R) receptors attract considerable interest from the medicinal chemistry community. Given their relatively high homology yet widely differing therapeutic promises, ligand selectivity for the two receptors is crucial. We interrogated H(4)R/H(3)R selectivities using ligands with a [1,2,3]triazole core. Cu(I)-assisted "click chemistry" was used to assemble diverse [1,2,3]triazole compounds (6a-w and 7a-f), many containing a peripheral imidazole group. The imidazole ring posed some problems in the click chemistry putatively due to Cu(II) coordination, but Boc protection of the imidazole and removal of oxygen from the reaction mixture provided effective strategies. Pharmacological studies revealed two monosubstituted imidazoles (6h,p) with <10 nM H(4)R affinities and >10-fold H(4)R/H(3)R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H(4)R with high steric precision. The use of the [1,2,3]triazole scaffold is further demonstrated by the notion that simple changes in spacer length or peripheral groups can reverse the selectivity toward H(3)R. Computational evidence is provided to account for two key selectivity switches and to pinpoint a lipophilic pocket as an important handle for H(4)R over H(3)R selectivity.

Retrospective Validation of a Structure-Based Virtual Screening Protocol to Identify Ligands for Estrogen Receptor Alpha and Its Application to Identify the Alpha-Mangostin Binding Pose

“…The modification in the SBVS protocol was using three independent molecular docking simulations for each compound instead of one as performed in the initial SBVS protocol [8]. One of the advantages of using some more independent simulations is that we can sample more converged docking poses for every compounds although it increases the computing cost [27,[30][31]. Fig.…”

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

“…The use of β2AR as a template for modelling of the H3 and H4 receptors is widely reported in the literature [86]. A post factum analysis suggest that the β2AR is similarly as good as H1 as a template for the modelling of H3 and H4.…”

Structure-based virtual screening for fragment-like ligands of the G protein-coupled histamine H4receptor

“…A second set of H 4 R models was built based on the recently solved H 1 R crystal structure (PDB-code 3RZE) 45 using Modeller (using the same protocol as the previously published β 2 R-based H 4 R model) 58,59,62 and subjected to the same optimization and validation protocols as the β 2 Rbased H 4 R homology models. The reference compounds were docked using PLANTS version 1.1 into the H 4 R binding pocket, which was defined using PLANTS bind tool.…”

“…Starting from a previously published 3D model of H 4 R, 58,59,62 based on the β 2 R crystal structure (PDB-code 2RH1), 44 new structural models of H 4 R were constructed and refined by docking and molecular dynamics simulations with three representative H 4 R ligands: Histamine (1), JNJ7777120 (2), and 5). The red bold numbers, the black bold numbers and the black regular numbers indicate the number of confirmed active hits (Tables 2 and 3), purchased hits (ESI † Figs.…”