A Quantitative Structure-Activity Relationship and Molecular Modeling Study on a Series of Biaryl Imidazole Derivatives Acting as H+/K+-ATPase Inhibitors

Neeraj Agarwal,Anubha Bajpai,Satya P Gupta,Vivek Srivastava

doi:10.1155/2013/810691

Abstract

The H+/K+-ATPase or proton pump is a magnesium-dependant enzyme which causes the exchange of a proton against a potassium ion through a membrane. Over activity of this enzyme causes hyperacidity by producing more of hydrochloric acid inside the stomach. This enzyme, therefore, has been found to be a good target for designing compounds to treat hyperacidity. A quantitative structure-activity relationship (QSAR) study has been made on a novel series of biaryl imidazole derivatives acting as H+/K+-ATPase inhibitors. The H+/K+-ATPase inhibition activity of these compounds is found to be significantly correlated with global topological charge indices (GTCIs) and the total polar surface area (TPSA) of the molecules, indicating the involvement of strong electronic interaction between the molecule and the receptor. Based on the correlations obtained, some new H+/K+-ATPase inhibitors are predicted. The docking studies of these predicted compounds exhibit that these compounds will have even better interaction with the receptor than those already marketed. Thus, they can prove more potent drugs for the treatment of hyperacidity.

Highlights

E hyperactivity of H+/K+-ATPase, the enzyme located in the parietal cells, is responsible for the nal step of acid secretion in the stomach, leading to many acid-related diseases, such as stomach and duodenal ulcers, symptoms of esophagitis, and severe gastroesophageal re ux disease (GERD), a condition where acid leaks up from the stomach into the esophagus. is enzyme is called proton pump
On a fairly large series of αα-amino acid derivatives, a quantitative structure-activity relationship (QSAR) study performed by Sharma et al [17] suggested that their pump inhibitors (PPIs) inhibition activity is controlled by the electronic properties, such as the energy of the highest occupied molecular orbital (EEHOMO), H-bond formation ability of some groups, and steric factors
Nobody has made any QSAR study on these compounds. e main objective of this study is to report the physicochemical properties that govern the activity of these compounds

Summary

Introduction

E hyperactivity of H+/K+-ATPase, the enzyme located in the parietal cells, is responsible for the nal step of acid secretion in the stomach, leading to many acid-related diseases, such as stomach and duodenal ulcers, symptoms of esophagitis (in ammation of esophagus, the tube from the mouth to the stomach), and severe gastroesophageal re ux disease (GERD), a condition where acid leaks up from the stomach into the esophagus. is enzyme is called proton pump. Ese authors reported QSARs on a series of 2,3-dihydropyrroloquinolines (3, Scheme 1) [13] and two different series of 2-guanidinothiazoles (4,5, Scheme 1) [14] In all their QSAR studies, these authors found the signi cant role of electronic properties of substituents, indicating that the overall electronic properties of molecules may be important for the inhibition of H+/K+-ATPase. On a fairly large series of αα-amino acid derivatives, a QSAR study performed by Sharma et al [17] suggested that their PPI inhibition activity is controlled by the electronic properties, such as the energy of the highest occupied molecular orbital (EEHOMO), H-bond formation ability of some groups, and steric factors. A docking study has been made of these new compounds and their results have been compared with those of licensed compounds. e ADME/T properties of these compounds have been studied and checked with the Lipinski rules

Objectives

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Results