Investigation Of Structure-based And Ligand-based Computer Aided Pesticide Bio-rational Design

With the fast development of resistance in the agricultural pests,stringent requirements of pesticide ecotoxicology and environmental compatibility,the conventional methods of pesticide design have exposed their deficiencies.Therefore,there is an urgent need for new theoretical methods and technical systems of current pesticide research.In this paper,we focused on the key scientific issues of pesticide development---"discovery and optimization of lead compounds".Based on the key physiological and biochemical processes in agricultural pests,the bio-rational design concept and computer-aided drug design method were employed to achieve the efficient screening and reasonable optimization of lead compounds via the structure-based or ligand-based design,and we strive to improve the technical system for the pesticide development of our country.The main contents were as follows:1)Janus kinase(JAK),the key protein in the JAK/STAT signaling pathway,was firstly employed as a potential fungicidal target.Based on the structure of JAK,a virtual screening method for the selective fungicidal lead compound was developed.Thus,a selective fungicidal lead compounds V4 were successfully identified,which displayed excellent in vitro fungicidal activity against Rhizoctonia solani,with EC50 value of 0.87 ?g/ml.Meanwhile,a promising anti-tumor JAK inhibitor V8 was identified.Molecular docking was implemented to elucidate the binding mode of the abovementioned lead compounds and the structural basis for their selective bioactivity.2)Succinate dehydrogenase(SDH),which is the key complex in the mitochondrial respiration chain,was selected as the target enzyme.Based on the analysis of the structural characteristic of current SDH inhibitors,a highly specific amide feature-based pharmacophore model was developed.A promising SDH inhibitor A16c with a novel pyrazol-benzoic scaffold was successfully identified via the integration of in silico library design.The lead compound A16c displayed improved in vitro fungicidal activity against Sclerotinia sclerotiorum(EC50 = 2.5 mg/L)and Phyricularia grisea(EC50 = 6.8 mg/L),and better in vivo activity against Phyricularia griseaat 200 mg/L in comparison with positive control thifluzamide.Besides,A16c exhibited promising inhibitory activity against SDH with IC50 value of 1.07?M.3)Scaffold hopping strategy was employed to optimize the carboxylic acid skeleton of lead compound A16c supported by structure-based drug design method.45 structurally novel pyrazole-furan carboxamide and pyrazole-pyrrole carboxamide derivatives have been designed and synthesized,and their structure-activity relationship has been thoroughly discussed,leading to the discovery of a secondary lead compound 12?-f.Compound 12?-f exhibited improved in vitro fungicidal activity against S.sclerotiorum and R solani compared with A16c,with EC50 of 1.2 and 0.5 mg/L,and better in vivo activity against S.sclerotiorum at 200 mg/L in comparison with positive control thifluzamide.4)Acetyl-CoA carboxylase(ACCase),which is the key enzyme employed in the lipid biosynthesis of insect,was selected as the research object.Based on the analysis of metabolism and mechanism of typical ACCase inhibitors,spirotetramat,the C8,C5'and C2' positions of spirocyclic tetronic acid skeleton were modified to improve its metabolic stability.To improve the rationality of molecular design,a support vector machine(SVM)classification model was developed to guide the rational optimization of lead compounds.Thus,we revealed that the introduction of oxime moiety to C5'positions or its cyclization was more favarable to improve the metabolic stability and bio availability without decrease of insecticidal activity of lead compound,providing guidance for the modification of the spirocyclic tetronic acid skeleton.