Design of Vonoprazan Pyrazole Derivatives as Potential Reversible Inhibitors of Gastric Proton Pump: An In Silico Molecular Docking Study

 Marko Karović¹, Boško Nikolić², Nikola Nedeljković¹, Marina Vesović¹, Miloš Nikolić¹

 

¹University of Kragujevac, Faculty of Medical Sciences, Department of Pharmacy, Kragujevac, Serbia
²University Clinical Center Kragujevac, Clinic for Gastroenterology and Hepatology, Kragujevac, Serbia

 

 SUMMARY

 

Introduction/Aim. Despite the fact that proton pump inhibitors are widely used for the 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. 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 of the distribution coefficient at physiological pH and pKa values. A 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 significant 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 a binding control. Based on the binding assessment criteria, these two compounds represent the molecules with the strongest inhibitory potential towards gastric proton pump.

 

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

 

 Corresponding author:
Miloš Nikolić
e-mail: milos.nikolic@fmn.kg.ac.rs