• CYP2C19;
  • molecular dynamics simulation;
  • proton pump inhibitors;
  • stereoselectivity

PPIs are mainly metabolized by CYP2C19. It has a stereoselectivity effect on R- and S-isomers of PPIs according to previous studies. However, no study has been reported to elucidate the binding mechanism at the atomic level based on the CYP2C19 crystal structure. Recently, the advent of the first crystal structure of CYP2C19 allowed us to take in silico approaches including MD simulation, MM/GBSA calculation, energy decomposition, and alanine scanning to explore the stereoselectivity of CYP2C19 on R- and S-isomers of PPIs. The key residues responsible for the selective binding for R- and S-isomers of omeprazole, lansoprazole, and pantoprazole are disclosed by free energy and alanine scanning analysis. Structural analysis showed that chiral isomers of PPIs alter their conformations to have strong binding affinities with CYP2C19. Furthermore, a theoretical pharmacophore model of PPIs was obtained with the importance of pharmacophore feature being weighted, basing on our results. Our results are valuable for designing and synthesizing new generation of PPIs in the future.