Inhibitors of cytochrome P450 catalyzed insecticide metabolism: A rational approach

✍ Scribed by György M. Keserü; István Kolossváry; István Székely

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 329 KB
• Volume: 73
• Category: Article
• ISSN: 0020-7608
• DOI: 10.1002/(sici)1097-461x(1999)73:2<123::aid-qua7>3.0.co;2-5

✦ Synopsis

The inhibition of cytochrome P450 mediated oxidative metabolism affected by methylenedioxyphenyl synergists was studied by theoretical methods. Binding w Ž . conformations of safrole-based inhibitors piperonyl butoxide PBO , safrole, and x izosafrole were obtained by the recently developed low-mode conformational search within the active site of cytochrome P450 . Increased activity of PBO was rationalized cam by the steric block created by its long side chain in the substrate access channel of the Ž . 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 Ž . was explored. Molecular dynamics MD simulations revealed that hydrogen bonding Ž . 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 NH...S hydrogen bonds with Gly359 and Leu358.