Protonated form: the potent form of potassium-competitive acid blockers.
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.
Hubei Key Laboratory of Natural Products Research and Development, College of Chemistry & Life Science, China Three Gorges University, Yichang, Hubei, China.
Hua-Jun
HJ
Luo
Hubei Key Laboratory of Natural Products Research and Development, College of Chemistry & Life Science, China Three Gorges University, Yichang, Hubei, China; Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China.
Wei-Qiao
WQ
Deng
Hubei Key Laboratory of Natural Products Research and Development, College of Chemistry & Life Science, China Three Gorges University, Yichang, Hubei, China.
Kun
K
Zou
D000818:Animals; D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D011188:Potassium / Q000737:chemistry*; D026902:Potassium Channel Blockers / Q000737:chemistry*; D011522:Protons; D055672:Static Electricity; D040681:Structural Homology, Protein
D026902:Potassium Channel Blockers; D011522:Protons; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium