ABSTRACT
316Detoxification enzymes play a role in defense systems against insecticides in insects including mosquitoes. The heme-containing cytochrome P450 monooxygenases (P450s), one of the major classes of insecticide detoxification enzymes, have been recognized as playing a key role in pyrethroid resistance in mosquitoes through their overexpression. Thus, inhibition of P450-mediated defense mechanisms may overcome or restrict insecticide resistance. Inhibitory compounds of P450 enzymes, in particular from plant sources, could serve as insecticide synergists to increase efficacy of insecticides and/or preserve the existent effective synthetic insecticides. Two mosquito P450s, CYP6AA3 and CYP6P7, were isolated from the deltamethrin-resistant Anopheles minimus malaria vector and have shown capability in pyrethroid metabolisms. Homology models of CYP6AA3 and CYP6P7 have been built and inhibition of both P450s by compounds of different chemical structures and compounds isolated from selected plant extracts have been reported. This chapter describes molecular docking to CYP6AA3 and CYP6P7 models and explores binding modes of enzyme models with pyrethroid and fluorescent substrates, as well as different inhibitory compound groups isolated from plant sources. We demonstrate that the amino acids within both enzyme pockets interact with various substrates and inhibitors. Structure–activity relationships of different chemical compound groups with inhibition effects and modes can be delineated and explained by molecular docking analysis. Insights into molecular mechanisms of interactions of natural compounds with both mosquito P450s can be valuable for the rational design of pyrethroid insecticide synergists and for insecticide resistance management control of malaria vectors.
