Histamine H₃ receptor ligands by hybrid virtual screening, docking, molecular dynamics simulations, and investigation of their biological effects

Abstract

Histamine H3 receptors (H3R), belonging to G‐protein coupled receptors (GPCR) class A superfamily, are responsible for modulating the release of histamine as well as of other neurotransmitters by a negative feedback mechanism mainly in the central nervous system (CNS). These receptors have gained increased attention as therapeutic target for several CNS related neurological diseases. In the current study, we aimed to identify novel H3R ligands using in silico virtual screening methods. To this end, a combination of ligand‐ and structure‐based approaches was utilized for screening of ZINC database on the homology model of human H3R. Structural similarity‐ and pharmacophore‐based approaches were employed to generate compound libraries. Various molecular modeling methodologies such as molecular docking and dynamics simulation along with different drug likeness filtering criteria were applied to select anti‐H3R ligands as promising candidate molecules based on different known parent lead compounds. In vitro binding assays of the selected molecules demonstrated three of them being active within the micromolar and submicromolar Ki range. The current integrated computational and experimental methods used in this work can provide new general insights for systematic hit identification for novel anti‐H3R agents from large compound libraries.

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes

“…Briefly, a combination of structure‐ and ligand‐based approaches was applied to search compounds from ZINC library on the homology model of the human H 3 R. Following the screening, the molecules were also inspected for drug‐likeness and ADME properties. Furthermore, the results of binding assays on selected compounds demonstrated that two compounds (i.e., compounds 3 and 4 ) were capable of binding to histamine H 3 Rs with K i values in submicromolar concentration range (Ghamari et al, ). In the current study, dual inhibitory activity of these compounds on H 3 Rs and cholinesterase enzymes was investigated.…”

“…According to the GI 50 values, the cytotoxic effect is more evident for compound 3 compared to the reference compound DX and therefore in agreement with the previously predicted in silico toxic potential. Based on the scale of toxicity alert, compound 4 was predicted to be a safe compound in comparison with compound 3 (Ghamari et al, ).…”

“…Compounds with ZINC IDs Zinc69700808 and Zinc90563066 were purchased from chemical suppliers of MolPort database (Riga, Latvia). Purity of the supplied compounds was evaluated by LC‐MS as described previously (Ghamari et al, ). Cyclic AMP XP Assay Kit (cat no.…”

“…A variety of molecular modeling techniques such as molecular docking and dynamics simulation, as well as drug‐likeness filtering criteria, were employed to select the candidate molecules. The selected compounds were experimentally evaluated using radioligand displacement studies, and the results revealed that two of them, obtained from the ligand‐based search method, were capable of binding to H 3 Rs in the submicromolar K i range (Ghamari et al, ). In the current work, we aimed to evaluate H 3 R antagonist/inverse agonist and anticholinesterase activity of the identified ligands with improved efficacy as a result of their synergistic activity.…”

A complex view of GPCR signal transduction: Molecular dynamics of the histamine H3 membrane receptor

“…Ghamari et al 62 built a 3D model of human and rat H3R (with N-ter absent and with ICL3 modeled as the lysozyme fusion protein in the crystal structure) by the homology comparative approach using the M3 muscarinic acetylcholine receptor in complex with tiotropium, a potent muscarinic inverse agonist (PDB Code 4DAJ). Thus, the model, just like the template receptor, is in the inactivated state.…”