Docking studies of novel pyrazinopyridoindoles class of antihistamines with the homology modelled H1-receptor

Abstract

Histamine is an important neurotransmitter as it controls a multitude of physiological functions by activating specific receptors on target cells. It exerts its effects by binding to four different histamine receptors (H1–H4), which all belong to the large family of G protein-coupled receptors (GPCRs). Research and development of H1 ligand has largely focused on antagonists which are used for their anti-allergy effects in the periphery. Recent understanding of the clinical importance of H1 receptors in brain, however, suggests the pharmacotherapeutic potential of H1 agonists in neurodegenerative and neuropsychiatric disorders. Despite the therapeutic importance of the H1 receptor, for many years the molecular features of the H1 receptor protein had been unknown. In view of the recently reported crystal structure of human H1 receptor and in continuation of our work on 3D-pharmacophore on antihistamine H1 and homology model of histamine H1 receptor, docking studies have been carried out on some promising pyrazinopyridoindole class of antihistamine H1, including two outliers, to validate our earlier reported models/hypotheses on H1-receptor, where a good explanation between estimated and observed activities has been obtained. In addition, the docking study also provided insights about the optimal activity of the outliers, for which no explanation was reported previously.