Identification of drug candidates against Histamine H3 receptors using drug repurposing strategy

Abstract

Over the past three decades, H3 receptors have attracted considerable attention due to their involvement in basic physiological functions such as wakefulness, circadian and eating rhythms, sensory and motor functions cognition, memory and learning. H3 receptors as autoreceptors of histaminergic system regulate the release of histamine and other neurotransmitters in the central nervous system. Blocking of centrally localized H3 receptors would enhance the level of histamine and other neurotransmitters in the brain. Therefore, H3 receptors are considered as potential therapeutic target in neuropsychiatric disorders. Aim:The purpose of the current study was to identify drug candidates against H3 receptors using drug repurposing strategy.Materials and Methods:In the current investigation, a combination of ligand- and structure-based methods were applied for identification of approved drugs against H3 receptors based on repurposing strategy. First, a QSAR model was generated using compounds with H3 antagonistic activity. Then, the developed QSAR model was utilized for predicting antagonistic activity of FDA-approved drugs. Therapeutic agents with higher predicted potencies were carefully scrutinized based on physicochemical and pharmacokinetic, drug-likeness, as well as medicinal chemistry properties. Drugs with desired properties were subjected to molecular docking and dynamics simulation for investigation of binding mode and affinity of the ligands towards H3 receptor using GOLD and AMBER programs. Molecular Mechanics (MM)-Poisson-Boltzmann Surface Area (PBSA)/Generalized-Born Surface Area (GBSA) methodologies implemented in AMBER package were applied for calculation of binding free energies. Results:Among the FDA-approved drugs, six drugs were introduced as the most suitable candidates in terms of predicted H3 antagonistic activity as well as pharmacokinetic and drug-likeness features. Conclusion:The results of the current study can offer some approved drugs to be useful in neuropsychiatric disorders. However, more preclinical bioassays both in in vitro and in vivo platforms are required to verify the in silico predictions.