Inhibitors of cytochrome P450 catalyzed insecticide metabolism: A rational approach

Abstract

ABSTRACT: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.

Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

“…26 An additional hypothesis reported by several authors is that the 425–427 nm peak is due to the carbine-induced displacement of the axial thiolate, leading to irreversible enzyme inactivation. 2, 27 Moreover, an additional peak at 438 nm was identified and attributed to a supposed oxidized cytochrome P450-metabolite (Fe 3+ :carbene). 25 …”

The use of substituted alkynyl phenoxy derivatives of piperonyl butoxide to control insecticide‐resistant pests

“…Piperonyl butoxide (PBO) and a few closely related MDP compounds such as sesame oil, isosafrole and safrole have demonstrated potent synergistic effects. However, PBO is one of very few in commercial use and is the leading insecticide synergist . Sesamex has a structure similar to PBO, but, although it was one of the first potent synergists reported, it failed to achieve commercial use owing to its instability in the presence of sunlight and moisture, decomposing to yield objectionably coloured products …”

“…However, PBO is one of very few in commercial use and is the leading insecticide synergist. 6,7 Sesamex has a structure similar to PBO, but, although it was one of the first potent synergists reported, 8 -11 it failed to achieve commercial use owing to its instability in the presence of sunlight and moisture, decomposing to yield objectionably coloured products. 5 Both Meligethes aeneus resistance to pyrethroids and Myzus persicae resistance to imidacloprid have been reported to be due to the activity of specific P450s, CYP6B23 and CYP6CY3 respectively.…”

Structure–activity relationship study of alkynyl ether insecticide synergists and the development of MB‐599 (verbutin)

“…PBO was much less effective, the LD 50 values against CHXSEL, MD‐IX and CARBSEL (1044, 450 and 7500 ng per fly) being a magnitude higher than the original LD 50 dose of 174 ng per WHO/SRS sensitive fly. The results also indicate that the precise mode of action of verbutin differs from that of PBO, which is characterised as an irreversible CYP450 suicide inactivator 26. 32…”

“…The calculations were carried out according to the method detailed in References 12 and 26, by simplified molecular docking calculations with a mathematical model of the central region of CP450 cam enzyme using SYBYL 6.1 (Tripos, St Louis, MO, USA) software.…”