A high degree of selectivity toward the target site of the pest organism is a desirable attribute for new safer agrochemicals. To assist in the design of novel herbicides, we determined the crystal structures of the herbicidal target enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27) from the plant Arabidopsis thaliana with and without an herbicidal benzoylpyrazole inhibitor that potently inhibits both plant and mammalian HPPDs. We also determined the structure of a mammalian (rat) HPPD in complex with the same nonselective inhibitor. From a screening campaign of over 1000 HPPD inhibitors, six highly plant-selective inhibitors were found. One of these had remarkable (>1600-fold) selectivity toward the plant enzyme and was cocrystallized with Arabidopsis HPPD. Detailed comparisons of the plant and mammalian HPPD-ligand structures suggest a structural basis for the high degree of plant selectivity of certain HPPD inhibitors and point to design strategies to obtain potent and selective inhibitors of plant HPPD as agrochemical leads.

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Similarities and differences between steric and electrostatic potentials of a monoclonal-antibody-based surrogate of a herbicide target-site and its in vitro enzyme target were investigated using three-dimensional quantitative structure-activity relationship comparative molecular field analysis (3D-QSAR CoMFA). Two separate, five-component, partial least squares CoMFA models were developed to compare the interaction of cyclohexanedione herbicides with their target site, acetyl coenzyme-A carboxylase (ACCase; EC 6.4.1.2) and a cyclohexanedione pharmacophore-specific monoclonal antibody (mAb A). On the basis of CoMFA models, similarities in steric and electrostatic requirements around position 2 of the binding site for the oxime functional group of the cyclohexanedione molecule appear to be crucial for interaction of the herbicide with both ACCase and mAb A. These similarities explain the observed quantitative relationship between binding of cyclohexandedione herbicides to ACCase mAb A. Furthermore, these results support the production and use of mAb-based surrogates of pesticide targets as screening tools in pesticide discovery programs.

Molecular modeling was used to propose an "active conformation" for the R-2-phenoxypropionic acid portion of the aryloxyphenoxypropionic acid series of herbicidal acetyl CoA carboxylase (ACCase) inhibitors. This candidate active conformation is a low-energy conformer with the R-methyl distal to the phenoxy fragment, stabilized by the generalized anomeric effect around the propionate ether bond; the inactive S-enantiomer has difficulty accessing this conformation due to steric interaction of the S-methyl with the o-hydrogen of the phenyl. This candidate conformation was challenged by preparation of a series of novel rigid analogues. ACCase inhibition data suggest that the systems which contain a fused five-membered, but not a six-membered, ring present the necessary pharmacophore to the active site of ACCase, confirming the active conformation hypothesis and demonstrating that the precise placement of the carboxylate relative to the phenyl group is more critical than the placement of the methyl.

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