Development of a general quantum‐chemical descriptor for steric effects: Density functional theory based QSAR study of herbicidal sulfonylurea analogues

Abstract

Quantitative structure-activity relationship (QSAR) analysis has become one of the most effective approaches for optimizing lead compounds and designing new drugs. Although large number of quantum-chemical descriptors were defined and applied successfully, it is still a big challenge to develop a general quantum-chemical descriptor describing the bulk effects more directly and effectively. In this article, we defined a general quantum-chemical descriptor by characterizing the volume of electron cloud for specific substituent using the method of density functional theory. The application of our defined steric descriptors in the QSAR analysis of sulfonylurea analogues resulted in four QSAR models with high quality (the best model: q2 = 0.881, r2 = 0.901, n = 35, s = 0.401, F = 68.44), which indicated that this descriptor may provide an effective way for solving the problem how to directly describe steric effect in quantum chemistry-based QSAR studies.

Insight into herbicide resistance of W574L mutant Arabidopsis thaliana acetohydroxyacid synthase: molecular dynamics simulations and binding free energy calculations

“…Although the resistance mechanisms for most of resistan weed species are unknown now, two mechanisms are proposed and generally accepted [7,8]: one is due to an altered target site, namely, point mutations occurring on specific conserved residues of AHAS resulting in insensitivity to herbicides, and this mechanism has been assigned to about 27 resistant weed species; the other is due to an enhanced metabolism of the herbicides, and this mechanism is only assigned to 3 resistant weed species. To overcome the herbicide resistance of this family, it is very imperative to understand the detailed interaction mechanism and resistance mechanism to direct the development of new potent inhibitors for wild-type or resistant AHAS, which is exactly the objective of our previous work [9][10][11][12][13][14][15][16] and present study.…”

Homologous and heterologous interactions between catalytic and regulatory subunits of Escherichia coli acetohydroxyacid synthase I and III

“…As one of the most important targets for inhibitors to be used as herbicides, AHAS has attracted a great deal of interest [4][5][6][7][8][9][10] . AHAS from E. coli has been most thoroughly studied.…”

Inhibitors of Bacillus anthracis acetohydroxyacid synthase

“…Pyrimidinylthiobenzoates [4] and phthalazin-1(2H)-one derivative [5] also constitute an important kind of herbicides targeting acetohydroxyacid synthase. Xi et al [6] have described a general quantum chemical descriptor for sulfonylurea analogues by characterizing the volume of electron cloud for specific substituent using the method of density functional theory. Until recently, amino acid biosynthesis has not been considered for antibacterial targeting because amino acids were assumed to be freely available to intracellular pathogens from their hosts.…”