Protonated form: the potent form of potassium-competitive acid blockers.

Hua-Jun Luo,Wei-Qiao Deng,Kun Zou,Freddie Salsbury

doi:10.1371/journal.pone.0097688

Abstract

Potassium-competitive acid blockers (P-CABs) are highly safe and active drugs targeting H+,K+-ATPase to cure acid-related gastric diseases. In this study, we for the first time investigate the interaction mechanism between the protonated form of P-CABs and human H+,K+-ATPase using homology modeling, molecular docking, molecular dynamics and binding free energy calculation methods. The results explain why P-CABs have higher activities with higher pKa values or at lower pH. With positive charge, the protonated forms of P-CABs have more competitive advantage to block potassium ion into luminal channel and to bind with H+,K+-ATPase via electrostatic interactions. The binding affinity of the protonated form is more favorable than that of the neutral P-CABs. In particular, Asp139 should be a very important binding site for the protonated form of P-CABs through hydrogen bonds and electrostatic interactions. These findings could promote the rational design of novel P-CABs.

Highlights

The gastric H+,K+-ATPase, primarily responsible for gastric acid secretion, is the key therapeutic target for the ulcer diseases such as duodenal ulcers, gastric ulcers, gastro esophageal reflux disease (GERD), Zollinger-Ellison syndrome (Z-E), and gastritis [1,2,3]
Homology modeling The sequences of the human (1035 amino acids) and pig (1033 amino acids) gastric H+,K+-ATPase receptor were taken from the Swiss-Prot Database (ID: P20648 and P09626) [34]
The results demonstrate that the hydrogen bond and electrostatic interactions with Asp139 should be very important for Potassium-competitive acid blockers (P-CABs) binding to H+, K+-ATPase, which are in agreement with the reference [62]

Summary

Introduction

The gastric H+,K+-ATPase (proton pump), primarily responsible for gastric acid secretion, is the key therapeutic target for the ulcer diseases such as duodenal ulcers, gastric ulcers, gastro esophageal reflux disease (GERD), Zollinger-Ellison syndrome (Z-E), and gastritis [1,2,3]. By cyclic phosphorylation and dephosphorylation of the catalytic subunit, H+,K+-ATPase undergoes conformational changes between E1 and E2. H+,K+-ATPase E1 conformation binding hydronium ion E1PNH3O+ changes to E2PNH3O+ form. After release of H3O+ and binding of K+ on the extracytoplasmic surface, the E2PNK+ conformation is formed and converts to the E1K conformation with the dephosphorylation. The E1K conformation releases K+ to the cytoplasmic side, rebinding of H3O+ occurs to complete the transition cycle [6]. The H+, K+-ATPase engages in 2K+/2H+/1ATP electroneutral ion exchange, generating a million-fold H+-gradient across the mammalian canalicular membrane of the parietal cell [7,8]

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Conclusion