A Quantitative Structure-Activity Relationship and Molecular Modeling Study on a Series of Heteroaryl- and Heterocyclyl-Substituted Imidazo[1,2-a]Pyridine Derivatives Acting as Acid Pump Antagonists
A quantitative structure-activity relationship (QSAR) and molecular docking study has been performed on a series of heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine derivatives acting as acid pump antagonists in order to have a better understanding of the mechanism of H+/K+-ATPase inhibition. The QSAR study shows a significant correlation of activity with Global Topological Charge Indices (GTCI) of the compounds and the hydrophobic constant of some substituents, indicating that the charge transfer within the molecule and the hydrophobic property of some substituents will be the controlling factor of the activity of these compounds and that there can be dispersion interaction between the molecules and the receptor, where some substituents may have hydrophobic interaction, too. Based on this correlation some new compounds with higher potency have been predicted and their docking study has been performed to see if they can have better interaction with the receptor. The ADME properties of these predicted compounds have also been reported that follow Lipinski’s rule of five. 1. Introduction Gastric H+/K+-ATPase is a member of the class 2C P-type ion-transport ATPases. It is present in the apical membranes of the parietal cells and is required for acid secretion. Gastric acid is necessary for sterilization and digestion of food and is specially required for the activity of pepsin through the activation of pepsinogen [1]. The H+/K+-ATPase couples the free energy of ATP hydrolysis for the establishment of the electrochemical gradients for H+ across the plasma membrane. Hyperactivity of H+/K+-ATPase results in overproduction of acid, leading to the gastroesophageal reflux disease (GERD), a condition in which acid leaks into the esophagus from stomach. To treat the hyperacidity and GERD, therefore, the potent inhibitors of H+/K+-ATPase are desired [2]. H+/K+-ATPase inhibitors elicit their inhibitory action by binding to the target protein in irreversible manner [3]. The proton pump inhibitors (PPIs) show their inhibitory action against H+/K+-ATPase by binding to the target protein in irreversible manner [3]. However, there are certain limitations of PPIs in the treatment of GERD and needs some alternative options to cure this disease [2, 3, 5]. Consequently, some potassium-competitive acid blockers (P-CABs), acting as acid pump antagonists, were studied to overcome these limitations of PPIs [2, 6, 7]. P-CABs are more active to achieve faster inhibition of acid secretion and longer duration of action as compared to PPIs, resulting in quicker symptom
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