Identification and in silico prediction of metabolites of the model compound, tebufenozide by human CYP3A4 and CYP2C19

Bioorg Med Chem. 2015 Oct 15;23(20):6594-601. doi: 10.1016/j.bmc.2015.09.019. Epub 2015 Sep 11.

Abstract

The metabolites of tebufenozide, a model compound, formed by the yeast-expressed human CYP3A4 and CYP2C19 were identified to clarify the substrate recognition mechanism of the human cytochrome P450 (CYP) isozymes. We then determined whether tebufenozide metabolites may be predicted in silico. Hydrogen abstraction energies were calculated with the density functional theory method B3LYP/6-31G(∗). A docking simulation was performed using FRED software. Several alkyl sites of tebufenozide were hydroxylated by CYP3A4 whereas only one site was modified by CYP2C19. The accessibility of each site of tebufenozide to the reaction center of CYP enzymes and the susceptibility of each hydrogen atom for metabolism by CYP enzymes were evaluated by a docking simulation and hydrogen abstraction energy estimation, respectively.

Keywords: CYP2C19; CYP3A4; Docking simulation; Hydrogen abstraction energy; In silico prediction; Tebufenozide metabolites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation*
  • Cytochrome P-450 CYP2C19 / metabolism*
  • Cytochrome P-450 CYP3A / metabolism*
  • Humans
  • Hydrazines / analysis*
  • Hydrazines / metabolism*
  • Molecular Docking Simulation
  • Software

Substances

  • Hydrazines
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • tebufenozide