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

• Published in: PloS one Vol. 9; no. 5; p. e97688
• Main Authors: Luo, Hua-Jun, Deng, Wei-Qiao, Zou, Kun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.05.2014; Public Library of Science (PLoS)
• Subjects: Acids; Amino acids; Animals; Antacids; ATPases; Binding sites; Biochemistry; Biology and Life Sciences; Cabs; Chemical bonds; Chemistry; Competition; Drug delivery; Electrostatic properties; Free energy; H(+)-K(+)-Exchanging ATPase - chemistry; Homology; Humans; Hydrogen; Hydrogen bonding; Hydrogen bonds; Laboratories; Life sciences; Ligands; Mechanics; Medicine and Health Sciences; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Natural products; Phosphorylation; Physical Sciences; Potassium; Potassium - chemistry; Potassium Channel Blockers - chemistry; Protein kinase A; Proteins; Protons; R&D; Research & development; Static Electricity; Structural Homology, Protein; Ulcers; New York; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0097688

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.