Design of vonoprazan pyrazole derivatives as potential reversible inhibitors of gastric proton pump: an in silico molecular docking study

Marko  Karović; Boško Nikolić; Nikola Nedeljković; Marina Vesović; Miloš Nikolić

doi:10.5937/afmnai41-43298

Marko Karović Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
Boško Nikolić Clinic for Gastroenterology and Hepatology, University Clinical Center Kragujevac, Kragujevac, Serbia
Nikola Nedeljković Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
Marina Vesović Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
Miloš Nikolić Fakultet Medicinskih Nauka, Univerziteta u Kragujevcu

DOI: https://doi.org/10.5937/afmnai41-43298

Keywords: proton pump inhibitors, distribution-based design, vonoprazan derivatives, pyrazole, molecular docking

Abstract

Introduction: Despite the fact that proton pump inhibitors are widely used for inhibition of gastric acid secretion, recent studies have revealed certain long-term side effects. Due to acidic environment in the stomach, it is challenging to design new competitive inhibitors of gastric proton pump with more potent inhibition of gastric acid secretion to conventional drugs.

Aim: The aim of this in silico study was to assess the potential of designed vonoprazan derivatives to inhibit the gastric proton pump using molecular docking study.

Methods: The distribution-based design of the vonoprazan derivatives was carried out by optimization the distribution coefficient at physiological pH and pK_a value. Molecular docking study was performed using the protein structure of gastric proton pump (PDB ID: 5YLU) in complex with vonoprazan in AutoDock Vina software.

Results: According to the estimated values of docking scores, derivatives 11, 21, and 25 showed the highest binding affinity to gastric proton pump. Compounds 3, 13, 14, 16, 17, 20, 22, and 23 formed the highest number of key binding interactions with the active site of proton pump.

Conclusion: Based on the obtained binding parameters, it can be concluded that derivatives 14 and 23 achieved the highest number of significant binding interactions (16 and 15, respectively) with concomitant lower values of the docking scores (-9.2 and -9.3 kcal/mol) compared to vonoprazan as binding control. Based on binding assessment criteria, these two compounds represent the molecules with the strongest inhibitory potential towards gastric proton pump.

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