Abstract
The inhibition of cytochrome P450 mediated oxidative metabolism affected by methylenedioxyphenyl synergists was studied by theoretical methods. Binding conformations of safrole-based inhibitors [piperonyl butoxide (PBO), safrole, and izosafrole] were obtained by the recently developed low-mode conformational search within the active site of cytochrome P450cam. Increased activity of PBO was rationalized by the steric block created by its long side chain in the substrate access channel of the enzyme. Stability of the Fe(II)–carbene complex was confirmed by quantum chemical calculations. In addition to the effect of back-donation, the role of the carbene orientation was explored. Molecular dynamics (MD) simulations revealed that hydrogen bonding between the carbene oxygen and Thr252-OH might stabilize the Fe(II) complex. Changes in the coordination of axial thiolate during carbene complexation were found to be crucial for the inhibitory action. Decreasing redox potential of the enzyme is caused by the increasing thiol character of the proposed drifting of the axial ligand stabilized by NHS hydrogen bonds with Gly359 and Leu358. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 123-135, 1999
Published Version
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