title: Rational design and screening study of novel lead compound based on acetohydroxyacid synthase structure.
abstract: Acetohydroxyacid synthase (AHAS) is a key target and has extensive application in the process of herbicide discovery. However, the problem of weed resistance is gradually serious with long-term excessive use of commercial AHAS-inhibiting herbicides, and so, it is urgent to develop novel herbicides. In this study, a virtual screening was performed based on the active site of AHAS. Then, the hit-10 compound with the IC50 value of 47.41 mg/L was selected as lead compound based on the biological testing. Subsequently, the optimization design and syntheses of lead compound were carried out according to the analyzing results of mechanism and receptor-/ligand-binding mode. Three novel 5-substituted benzyl-1,3,4-thiadiazol-2-carbamic acid phenyl ester derivatives were designed and synthesized. Bioactive assay results of the three target compounds showed that all of them displayed the higher inhibition than lead compound to AHAS, with the IC50 values in the 23.54-32.05 mg/L range, and the inhibition rates were increased by 30-50%. Finally, we also analyzed the possible inhibitory mechanism of the three target compounds based on the molecular docking between AHAS and target compounds. This study would provide a novel chemical structure for the discovery of novel AHAS herbicides.
authors.affiliation: College of Science, Huazhong Agricultural University, Wuhan, 430070, China.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Jin
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Qi
authors.forename: Dandan
authors.initials: D
authors.lastname: Yao
authors.forename: Bangqiang
authors.initials: B
authors.lastname: Mao
authors.forename: Jianhong
authors.initials: J
authors.lastname: Li
authors.forename: Qingye
authors.initials: Q
authors.lastname: Zhang
authors.forename: Changshui
authors.initials: C
authors.lastname: Chen
mesh_terms: D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D006540:Herbicides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D006540:Herbicides; D000095:Acetolactate Synthase
keywords: acetohydroxyacid synthase; bioactive assay; lead compound optimization; synthesis; virtual screening