Interactions Between AHAS And Structurally Diverse Inhibitors

Design and synthesis of novel highly selective and potent herbicides with acetohydroxyacid synthase (AHAS) as target is one of the most important area in herbicidal research. Four herbicidal families have been known as AHAS-inhibitors: sulfonylurea (SU), imidazolinone (IM), triazolopyrimidine (TP) and pyrimidinyl(oxy)thiobenzoic acid (PTB). The crystal structures of the catalytic subunit of AHAS in complex with sulfonylurea and imidazolinone have been determined respectively which settle a solid experimental basis for understanding the detailed intermolecular interactions between them and the enzyme. But the binding models of the other two herbicide families are still unknown. In this dissertation, 3D-QSAR, molecular dynamics simulation and binding free energy calculation were used to study the interactions between the enzyme and triazolopyrimidine and pyrimidinyl(oxy)thiobenzoic acid respectively.Comparing different optimizing methods and charges, which showed that the high accurate DFT method with electrostatic potential (ESP)-fitting charges did better for constructing highly reliable CoMFA and CoMSIA models. This result afforded a new approach to 3D-QSAR research in future. The model based on this method and charges could be interpreted in protein structural terms and could be used to predict the activity of new molecules with similar strctures as a good predictive tool.The interactions between AHAS and structurally diverse inhibitors—pyriminobac-methyl, flumetsulam, a new active compound Y4311 were studied systemically by using molecular dynamics simulation (MD) and binding free energy calculation. The binding model of pyriminobac-methyl agreed with the 3D-QSAR results. The VDW, electrostatic and H-bond interactions were analyzed in detail, and the H-bonds between pyriminobac-methyl and Gly657, flumetsulam and Gly116 were found in the trajectory of MD. The location and orientation of pyriminobac-methyl, flumetsulam, Y4311 were determined in the binding site, and the similarities and differences were compared and discussed, which provided lots of imformation for further novel potent inhibitors design definitely.With the imformation from the interactions between these inhibitors and AHAS, 14 new compounds were synthesized and the compound II-3 showed moderate inhibitory activity to the E. coli widetype and W464L AHAS. The structure of this compound can be optimized further as a lead compound.