In-silico approach for designing novel urea/thiourea and schiff base of quinazolinone derivatives of molecular docking H+/K+-ATPase inhibitors

Abstract

Abstract H+/K+-ATPase (Proton Pump) is responsible for acid production from parietal cells of stomach. Acid-related disorders are caused by uncontrolled activity of proton pumps. Inhibition of these proton pumps has been shown to be effective in the treatment of GERD (Gastro-oesophageal reflux disease). Our aim was to investigate the effective proton pump inhibitor and prediction of the best analogues. Quantitative structure Activity Relationship (QSAR) was performed on two sets of molecules, i.e.,\xa0on tert-Butyl1, 5- bis(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1,5-dioxopentan-2-ylcarbamte urea/thio-urea derivatives and schiff base of quinazolinone derivatives. Biological activity for H+/K+-ATPase inhibition was found to be significantly correlated with polarizability and surface tension (ST) for the first set of analogues and with polar surface area (PSA), polarizability and hydrophobic constant for the second set of analogues, indicating the involvement of strong electronic interaction between the molecule and the receptor. Based on the correlations obtained from the schiff’s base derivatives by the QSAR model, new H+/K+-ATPase inhibitors were predicted. Based on the generated QSAR Model, a series of new compounds were designed. Afterwards, these compounds were docked with the protein and their ADME properties were evaluated. Toxicity of these new analogues was also predicted. The QSAR studies were not performed on both sets of analogues previously. Present study predicts more potent, less toxic, easily synthesisable lead molecules.