Eco-friendly insecticides have received global attention in recent years. How is it possible to avoid the potential ecological risk in the initial phase of insecticide discovery? In this study, Manduca sexta was selected as a model insect, molecular evolution studies and structural analysis of HMG-CoA reductase (HMGR), which is a core enzyme of the biosynthesis pathway of juvenile hormone (JH) in insects, were used to do qualitative and quantitative analysis of the eco-friendly prediction of targets at the first step. Based on the difference of sequence and structures, 20 HMGR inhibitors were designed with virtual screening using the Unity program in Sybyl. All the compounds were synthesized, and their effects on JH biosynthesis of M. sexta were tested. 15 compounds have good bioactivities, their IC50 values ranged from 3 nM to 1 �M. We also tested the effects on human HMG-CoA reductase of all the 15 compounds. 5 compounds have no effects to the human enzyme, and 2 compounds were 10-fold less potent for human than for M. sexta. Those 7 compounds also have good effects in vivo. Their oral toxicity IC50 values for M. Sexta are 5-50 �M. The IC50 values of compound A for ovicidal action are 1 �M. Some of the inhibitors have abilities as insect growth regulators. Our results show that insect HMGR can be an eco-friendly insecticide target. We also proved that molecular evolution, homology modeling and structural comparison can be used to do qualitative and quantitative analysis of the eco-friendly prediction of target molecules.

Discovery of eco-friendly insecticides based on the molecular evolution and structure comparison analysis of HMG-CoA reductase

248th National Meeting (2014)

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