Design of novel ligand(s) against the histamine H4 receptor based on scaffold hopping method

Abstract

Introduction: Histamine receptors are a class of G protein-coupled receptors (GPCRs), which are activated by binding of histamine. Histamine is a mediator that plays a crucial role in various physiological and pathophysiological processes through its receptors. The most recently discovered histamine H4 receptor (H4R) is distributed in different tissues mainly found in immune cells. H4R is closely related to the immune response in various diseases such as autoimmune disease, cancer, inflammatory and allergic diseases. Considering the therapeutic potential of the H4R, designing novel H4 receptor antagonist is of great importance in H4 related diseases. Aims: The aim of this thesis was to identify novel histamine H4 receptor ligands through the scaffold hopping methodology using adriforant and toreforant as lead compounds.Materials and methods: In the present study, structure-based approaches were utilized to design novel H4 antagonists. For this purpose, adriforant and toreforant were used as starter molecules for bioisosteric replacement search available in the Spark program. Different filtering criteria such as physicochemical, pharmacokinetic, and drug-likeness were applied on the library of the compounds. Subsequently, the molecular docking experiment was conducted to predict the binding mode of chosen compounds with the target receptor. Then, molecular dynamics simulation studies were performed on the complex of docked ligands and receptor for 50ns followed by binding free energy calculation using MM-PBSA and MM-GBSA algorithms.Results: Among the designed compounds, five compounds were selected as new chemical entities based on predicted physicochemical, pharmacokinetic and drug-likeness properties. Among them, T2 seems the most suitable compound for further evaluations.Discussion: The results of the present study propose new scaffolds and structures that can be synthesized as H4R ligands and evaluated for in vitro and in vivo studies.