Discovery of novel potassium-competitive acid blockers: Protonated form of ligand-receptor complex system

Potassium-competitive acid blockers (P-CABs) are acid-suppressing drugs targeting the gastric proton pump (H+,K+-ATPase). They are able to mediate the electro-neutral exchange of H+ and K+ coupled with ATP hydrolysis. Because the conditions of both the cytoplasmic side (pH ∼7) and extracytoplasmic side (pH ∼1) of the target H+,K+-ATPase is are quite different, putting into consideration the moderate protonated forms of both the target protein and the P-CABs is important for system modeling. The three different protonated forms of the receptor models were evaluated with experimental data using docking and molecular dynamics. Here, we utilized the in-silico approaches to discover possible inhibitors against H+,K+-ATPase. Candidate substances were screened from the ChEMBL, Enamine, and Mcule databases. The high-throughput virtual screening (HTVS) was performed to screen for potent compounds. Molecular dynamics (MD) simulations were carried out among high docking scored candidates to validate the stability and binding affinity. These findings show that the proper modeling of the target-ligand complex is important for screening potent compounds, especially in extreme environments.