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

摘要

Seventy-four sulfonylureas were synthesized and tested for their inhibitory activity against the wholeenzyme of E. coli acetohydroxyacid synthase (AHAS, EC 2.2.1.6) isoenzyme II, and 3D-QSAR analyseswere performed based on these inhibitory activities. The binding conformation of chlorimuron-ethyl, acommercial herbicide of AHAS, in the crystal structure of AHAS complex was extracted and used astemplate to build the initial three-dimensional structure of other sulfonylureas, and then all structureswere 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~2_(pred)= 0.832; CoMSIA: q~2= 0.721, r~2= 0.913, n = 8, r~2_(pred)= 0.844) were estab-lished. By mapping the 3D contour maps of CoMFA and CoMSIA models into the possible inhibitoryactive site in the crystal structure of catalytic subunit of yeast AHAS, a plausible binding model forAHAS, with best fit QSAR in the literature so far, was proposed. Moreover, the results of 3D-QSAR werefurther utilized to interpret resistance of site-directed mutants. A relative activity index (RAI) for AHASenzyme mutant was defined for the first time to relate the 3D-QSAR and resistance of mutants. Thisstudy, for the first time, demonstrated that combination of 3D-QSAR and enzyme mutation can be usedto 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.