Interactions of omeprazole-based analogues with cytochrome P450 2C19: a computational study

Abstract

Cytochrome P450 2C19 (CYP2C19) is one of 57 drug metabolizing enzymes in humans and is responsible for the metabolism of ∼7-10% of drugs in clinical use. Recently omeprazole-based analogues were reported to be the potent inhibitors of CYP2C19 and have the potential to be used as the tool compounds for studying the substrate selectivity of CYP2C19. However, the binding modes of these compounds with CYP2C19 remain to be elucidated. In this study, a combination of molecular docking, molecular dynamics (MD), and MM/GBSA calculations was employed to systematically investigate the interactions between these compounds and CYP2C19. The binding modes of these analogues were analyzed in detail. The results indicated that the inclusion of explicit active site water molecules could improve binding energy prediction when the water molecules formed a hydrogen bonding network between the ligand and protein. We also found that the effect of active site water molecules on binding free energy prediction was dependent on the ligand binding modes. Our results unravel the interactions of these omeprazole-based analogues with CYP2C19 and might be helpful for the future design of potent CYP2C19 inhibitors with improved metabolic properties.

Computational insights into the different catalytic activities of CYP3A4 and CYP3A5 toward schisantherin E

“…Other parameters for docking were set to default. The criteria for selecting the representative poses were similar to our previous study (Li, Cai et al., ; Li, Du et al., ). The criteria we adopted are as follows: (a) the distance between the site of metabolism (SOM) and the O atom of CpdI is within 6 Å (Hritz, de Ruiter, & Oostenbrink, ); (b) the experimental SOM of the given pose orients to the O atom of CpdI; and (c) the docking score of the pose is at the top ranking.…”

“…The detailed MD simulation procedure was adopted as described in our previous work (Li et al., ; Li, Cai et al., ; Li, Du et al., ). In brief, all water molecules and hydrogen atoms were optimized at first.…”

“…So far, several GB models have been developed and implemented in amber . According to our previous study (Li, Cai et al., ; Li, Du et al., ), the GB n1 model (igb = 7) (Mongan, Simmerling, McCammon, Case, & Onufriev, ) was used in this study. The binding free energies were also calculated by the MM/GBSA method.…”

“…The nonpolar solvation energy (∆ G nonpol ) was solved using the LCPO algorithm (Weiser, Shenkin, & Still, ) from the solvent‐accessible surface area (SASA, Å2). The coefficient surface tension γ and constant b were set to 0.0072 kcal mol −1 Å 2 and 0, respectively (Li, Cai et al., ; Li, Du et al., ). T ∆ S denotes the entropic contribution, which was estimated using the normal mode analysis in amber 16.…”

Computational research of mTORC1 inhibitor on cerebral ischemia-reperfusion injury

“…TOPKAT (Toxicity Prediction by Computer Assisted Technology) modules of DS 4.5 also play a vital role in evaluating the toxicity and other properties of all the potential compounds. The analysis of these two modules consists of their aqueous solubility, cytochrome P450 2D6 (CYP2D6) inhibition, plasma protein binding (PPB) level, blood-brain barrier (BBB) penetration, hepatotoxicity, human intestinal absorption, rodent carcinogenicity, AMES mutagenicity, rodent carcinogenicity and developmental toxicity potential [18]. Among them, plasma protein binding rate refers to the ratio of the amount of plasma protein binding to the total blood dose after the drug enters the blood.…”