Inhibitors of cytochrome P450 catalyzed insecticide metabolism: A rationalapproach

The inhibition of cytochrome P450 mediated oxidative metabolism affected by methylenedioxyphenyl synergists was studied by theoretical methods. Bindin g conformations of safrole-based inhibitors [piperonylbutoxide (PBO), safro le, and izosafrole] were obtained by the recently developed low-mode confor mational search within the active site of cytochrome P450(cam). Increased a ctivity of PBO was rationalized by the steric block created by its long sid e chain in the substrate access channel of the enzyme. Stability of the Fe( II)-carbene complex was confirmed by quantum chemical calculations. In addi tion to the effect of back-donation, the role of the carbene orientation wa s explored. Molecular dynamics (MD) simulations revealed that hydrogen bond ing between the carbene oxygen and Thr252-OH might stabilize the Fe(II) com plex. Changes in the coordination of axial thiolate during carbene complexa tion were found to be crucial for the inhibitory action. Decreasing redox p otential of the enzyme is caused by the increasing thiol character of the p roposed drifting of the axial ligand stabilized by NH...S hydrogen bonds wi th Gly359 and Leu358. (C) 1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 123-135, 1999.