Protonated Form: The Potent Form of Potassium-Competitive Acid Blockers

Hua-Jun Luo, Wei-Qiao Deng and Kun Zou

PLOS ONE, 2014, vol. 9, issue 5, 1-13

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.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0097688

DOI: 10.1371/journal.pone.0097688

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