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.

Keywords:

• H₁ antagonists
• doxepin
• homology model
• docking
• pharmacophore

Acknowledgements

S.S.B. is thankful to CSIR, New Delhi, for financial assistance in the form of a fellowship. M.S. is thankful to DST for financial assistance and to AVSM Major General K.K. Ohri, Director General and Prof. S.T.H. Abidi, Director ASET, Amity University, Lucknow campus for cooperation and support. The technical assistance of Mr. A.S. Kushwaha is also gratefully acknowledged. CDRI Communication number: 8211