Molecular dynamics study on Revaprazan and its analogue as potassium-competitive acid blockers

Fei Ren1, Zi-Qiang Wu1, Hua-Ju

Abstract

The interaction mechanisms of revaprazan and its analogue revaprazan-7h as potassium-competitive acid blockers (P-CABs) were studied by induced-fit docking, molecular dynamics and MM/GBSA binding free energy calculation methods. The order of favorable binding interaction is revaprazan-7h (neutral form) > revaprazan (protonated form) > revaprazan-7h (protonated form) > revaprazan (neutral form). The calculation results indicate that enlarging the binding region of ligand with H+,K+-ATPase (such as residues Thr134, Thr135, Asp137, Asn138, Trp899, Glu900, Gln924, Tyr928, Phe988 and Asn989) would increase the activity. Due to hydrogen bonds and electrostatic interactions, Asp137 in particular should be a very important binding site for protonated form of ligand. The findings could help for further rational design of novel P-CABs.