Discovery of Novel Ligands against Histamine H3 Receptors Based on Scaffold Hopping Method

Abstract

Histamine H3 receptor (H3R) belongs to G-protein coupled receptor (GPCR) family which is responsible for modulating the release of histamine as well as other neurotransmitters such as noradrenaline, acetylcholine, dopamine through a negative feedback mechanism. Since the discovery of H3R in 1983, this receptor has attracted much attention as therapeutic target for neurodegenerative diseases and currently there are several candidate molecules in different phases of clinical trials. Aim: The aim of present study was structural optimization of previously identified H3 antagonists in order to improve physicochemical and binding potencies using scaffold hopping method.

Materials and methods: By applying bioisosteric replacement, structural modification were performed on the previously identified bioactive compounds. Then, the designed compounds were inspected in terms of ADMET and drug-likeness properties. In the following step, molecular docking of the candidate molecules were performed into binding site of H3R to predict the mode of interactions between compounds and H3R. Then the docked ligands in complex with receptor were subjected to molecular dynamics (MD) simulation for simulation length of 50 ns with subsequent calculation of binding free energy using MM/GBSA and MM/PBSA algorithms.

Results: In silico analyses of the designed compounds showed that the candidates were optimized based on ADMET and drug-likeness properties. The results of the molecular docking revealed the important interactions between molecules and H3R. Analysis of MD simulations demonstrated that all systems in the simulation were well-equilibrated and remained stable throughout 50 ns simulation run.

Conclusion: The results of the current investigation can provide insights for systematic design of novel anti-H3R agent. The suggested compounds can be synthesized and biologically evaluated in near future with the aim of developing therapeutic agents beneficial in neurological disorders.