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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Semiempirical, molecular mechanics, and molecular dynamics calculations have been performed to theoretically examine the metabolism of 2-n-propylpentanoic acid (valproic acid, VPA), a widely used therapeutic agent for the control of seizure disorders, by cytochrome P450. In particular, the stereospecificity and product distribution of the hydroxylated metabolites of VPA are predicted for the P450,, isozyme and compared to the experimental data from microsomal P450. Quantum mechanical results are consistent with hypothesized mechanisms for the formation of 2-n-propyl-4-pentenoic acid (4-ene-VPA), a hepatotoxic metabolite, by a P450-catalyzed dehydrogenation reaction. The current theoretical results suggest that differences in the binding sites between mammalian P450 isozymes and P450,, may modulate the product distribution via steric interactions with the substrate.

I 1 inated with some monoradial impurities.I2 By using the equation (4) where I is the signal intensity calibrated with a reference TANOL, N , and N , are the respective amounts of monoradical and diradical, and AE is the energy gap between the singlet and the thermally excited triplet, N,, Nu, and AE were determined: N,,, = 2.0 X IO'' molecules/mol, Nu = 2.3 X 1OIs molecules/mol, and AE = 0.81 kcal/mol. The excited diradical contribution to the ground state of 1 is remarkably small (104-10-3%).The present finding provides a first instance of excited diradical contribution to the ground state of a closed-shell nonalternant hydrocarbon system, although this has already been known for quinodimethane and the quinone derivatives, Chichibabin's hyd r~c a r b o n , '~ and 2,5-bis(3,5-di-tert-butyl-4-oxocyclohexadienylidene)thieno[3,2-b] thiophene.14 Such a contribution should increase in the excited state; some useful applications of this unique physical property may be expected in the near future.

Esters of short chain aliphatic acids are commonly used in industry as solvents which are easily metabolized to their acid analogs. Some of these aliphatic acids are also by-products of industrial products, e.g., 2-ethyl hexanoic acid is a metabolite of the plasticizer diethylhexyl phthalate and methoxy acetic acid is the principal metabolite of the glyco ether, 2-methyl ethanol. Many of these aliphatic acids exhibit a variety of toxic effects. Cytochrome P450 is involved in the metabolism of aliphatic acids resulting in liver toxicity by formation of a toxic metabolite. These acids also act as sedatives, possibly by occupying a hydrophobic site in the brain. Certain aliphatic acids have been shown to cause teratogenic effects in laboratory animals for which the mechanism is as yet unknown. The techniques of computational chemistry can be useful in helping to formulate such mechanisms and ultimately for computer-aided risk assessment of potentially toxic compounds. The current study focuses on developing reliable molecular indicators of the teratogenic behavior of selected aliphatic acids, by investigating the role of conformational, physical, and electronic properties. The geometries of the aliphatic acids used for analysis were optimized using CHARMm and AM 1. Our results show that pK, and log P do not seem to be reliable modulators of teratogenic potency. By contrast, the conformation of the acid analogs, especially near the acid group, appears to be important for activity. These results implicate a possible mechanism of action involving a conformationally specific binding site or camer protein.