Discovery Of Eco-friendly Insecticides Based On The Sequence Alignments And Structure Comparative Analysis Of HMG-CoA Reductases

Pesticides can control crop disease,pets,and weeds effectively.They can save about 35%of total crop losses each year for the world,and restore the economic losses of up to$300 billion.The traditional insecticides have made an outstanding contribution to harvest and health.But due to the improper use and the inherent shortcomings of some insecticides,they result in a negative impact on the environment and ecology.Therefore,eco-friendly insecticides receive global attention in recent years.But how to avoid the potential ecological risk in the initial phase of insecticides discovery is a problem that has not fully solved up to now.HMGR inhibitors have been studied in the medical field for about 30 years.And some studies have shown that HMG-CoA reductase not only exists in mammals,but also presents in other animals,plants and bacterium.In this thesis,five insecticide targets(nAChR,GABAR,AChE,VGSCs and RyR)were first studied with sequence alignments,homology modeling and molecular docking.A prediction method was established for determining which enzyme or receptor can be eco-friendly pesticide target,using sequence alignments,homology modeling and molecular docking.Then this method was used to predict two main enzymes of JH biosynthesis pathway,HMGS and HMGR.The result showed that HMGR may be an eco-friendly candidate insecticide target.The JH biosynthesis inhibition was studied on M.sexta,A.melliefra and D.punctata with some commercial statin compounds(fluvastatin,pitavastatin and lovastatin).Results showed that there was significant inhibit effect on M.sexta,lower effect on D.punctata,and a little effect on A.mellifera.Then we designed a series of gem-difluoromethylene statin analogues.The JH biosynthesis inhibitions of these analogues were also studied.It showed that most of these compounds have effects to JH biosynthesis.The bioactivity of gem-difluoromethylene statin analog compound 1-7 was higher than its lead fluvastatin,which suggested our design idea was correct.After that,compound 1-7,fluvastatin,pitavastatin and lovastatin were tested the stomach toxicity,contact toxicity and killing eggs activity on M.sexta.The results showed that stomach toxicity and killing eggs activity were the important action way of those compounds.In this paper,a new JH biosynthesis assay was also established using GC-MS/MS.The standard deviation was the minimum when the incubation hour was 6 h.