A Quantitative Structure-Activity Relationship and Molecular Modeling Study on a Series of Biaryl Imidazole Derivatives Acting as H+/K+-ATPase Inhibitors
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. 1. Introduction The hyperactivity of H+/K+-ATPase, the enzyme located in the parietal cells, is responsible for the final step of acid secretion in the stomach, leading to many acid-related diseases, such as stomach and duodenal ulcers, symptoms of esophagitis (inflammation of esophagus, the tube from the mouth to the stomach), and severe gastroesophageal reflux disease (GERD), a condition where acid leaks up from the stomach into the esophagus. This enzyme is also called proton pump. Since it is unique to parietal cells, it is considered to be a good target for developing the drugs for curing acid-related diseases [2]. The design of proton pump inhibitors (PPIs) is focused on achieving long lasting and rapid inhibition of acid secretion [1]. The PPIs decrease the amount of acid produced in the stomach by inhibiting the function of the pump and are thus useful to treat GERD [3, 4]. The mechanisms of action of PPIs are focused on the final step of gastric acid secretion which are competitive with respect to？K+ binding to the parietal cell gastric H+/K+-ATPase [3, 5, 6]. There are also reversible PPIs that bind near the site of K+ channel and inhibit the action of H+/K+-ATPase [7, 8]. They are thus also called potassium-competitive acid blockers (P-CABs). The therapeutic action of these P-CABs is somewhat superior to that of PPIs in terms of faster mechanism of action and long duration, which result in quicker relief and healing [2, 3, 9,
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