Articles Chemical Biology

Chinese Science Bulletin

, Volume 52, Issue 14, pp 1929-1941

First online:

Study on structure-activity relationship of mutation-dependent herbicide resistance acetohydroxyacid synthase through 3D-QSAR and mutation

  • Yu ZhiHong Affiliated withState Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, Nankai University
  • , Niu CongWei Affiliated withState Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, Nankai University
  • , Ban ShuRong Affiliated withState Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, Nankai University
  • , Wen Xin Affiliated withState Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, Nankai University
  • , Xi Zhen Affiliated withState Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, Nankai University Email author 

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Abstract

Seventy-four sulfonylureas were synthesized and tested for their inhibitory activity against the whole enzyme of E. coli acetohydroxyacid synthase (AHAS, EC 2.2.1.6) isoenzyme II, and 3D-QSAR analyses were performed based on these inhibitory activities. The binding conformation of chlorimuron-ethyl, a commercial herbicide of AHAS, in the crystal structure of AHAS complex was extracted and used as template to build the initial three-dimensional structure of other sulfonylureas, and then all structures were fully geometry optimized. After systematic optimization of the alignment rule, molecular orientation, grid space and attenuation factor, two satisfactory models with excellent performances (CoMFA: q 2 = 0.735, r 2 = 0.954, n = 7, r pred 2 = 0.832; CoMSIA: q 2 = 0.721, r 2 = 0.913, n = 8, r pred 2 = 0.844) were established. By mapping the 3D contour maps of CoMFA and CoMSIA models into the possible inhibitory active site in the crystal structure of catalytic subunit of yeast AHAS, a plausible binding model for AHAS, with best fit QSAR in the literature so far, was proposed. Moreover, the results of 3D-QSAR were further utilized to interpret resistance of site-directed mutants. A relative activity index (RAI) for AHAS enzyme mutant was defined for the first time to relate the 3D-QSAR and resistance of mutants. This study, for the first time, demonstrated that combination of 3D-QSAR and enzyme mutation can be used to decipher the molecular basis of ligand-receptor interaction mechanism. This study refined our understanding of the ligand-receptor interaction and resistance mechanism in AHAS-sulfonylurea system, and provided basis for designing new potent herbicides to combat the herbicide resistance.

Keywords

sulfonylurea acetohydroxyacid synthase 3D-QSAR CoMFA CoMSIA site-directed mutation herbicide resistance