Molecular modelling studies on 2-substituted octahydropyrazinopyridoindoles for histamine H₂ receptor antagonism

^$Presented at the 8th International Symposium on Computational Methods in Toxicology and Pharmacology Integrating Internet Resources, CMTPI-2015, June 21–25, 2015, Chios, Greece.

Abstract

The human histamine H₂ receptor (hH₂HR) is a G-protein coupled receptor protein with seven transmembrane (TM)-spanning helices primarily involved in regulation of gastric acid secretion. Antagonists targeting hH₂HR are useful in the treatment of hyperacidic conditions such as peptic ulcers, gastresophageal reflux disease and gastrointestinal bleeding. We have previously reported the antagonism of 2-substituted pyrazinopyridoindoles at the human histamine H₁ receptor and mode of binding of these compounds at the hH₁HR using in silico methods. Interestingly, some of the compounds in the series also showed promising activity towards hH₂HR that prompted us to investigate the mode of binding of these compounds at hH₂HR. In the absence of the crystal structure of hH₂HR a homology model has been constructed using multiple sequence alignment, using the X-ray crystal structures of Turkey β₁-adrenergic receptor (tβ₁AR), Human histamine H₁ receptor (hH₁HR), Human β₂-adrenergic receptor (hβ₂AR) and Human D₃ dopamine receptor (hD₃R). The important residues for binding were depicted in TMIII, TMV, TMVI and TMVII by the homology modelled hH₂HR for 2-substituted pyrazinopyridoindoles. A comparative study for deducing the selectivity regarding the binding towards hH₁HR and hH₂HR has been carried out, which may be useful in designing of selective hH₁HR/hH₂HR antagonists in these classes of compounds.

Keywords:

• homology modelling
• histamine H₂ blocker
• antihistaminic H₂
• octahydropyrazino-pyridoindoles
• famotidine pharmacophore
• docking

Acknowledgements

M.S. is thankful to DST for financial assistance, CDRI for continuing the project 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.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes

^$ Presented at the 8th International Symposium on Computational Methods in Toxicology and Pharmacology Integrating Internet Resources, CMTPI-2015, June 21–25, 2015, Chios, Greece.