Structure-based design of inhibitors of the rice blast fungal enzyme trihydroxynaphthalene reductase.

Rice Blast Disease, caused by the fungus Pyricularia oryzae, is one of the most important diseases of rice. Several enzymes in the melanin biosynthetic pathway have proven to be valuable targets for development of rice blast fungicides. In particular, inhibitors of trihydroxynaphthalene reductase (3HNR), which catalyzes the conversion of trihydroxynaphthalene to vermelone, have yielded commercially useful rice fungicides. The X-ray structure of 3HNR has been published recently, presenting an opportunity to use this information in the de novo design of novel 3HNR inhibitors that may exhibit useful rice blast activity. We used the LeapFrog program to develop a docking model for interaction of ligands with the active site of THNR. The final model gave a good correlation between calculated binding energy and log Ki and was used to design novel ligands and score compounds for synthesis. Using this as a tool, we synthesized inhibitors in the nanomolar range and also developed several inhibitors that did not conform to the properties of the THNR active site. Leapfrog was able to locate a previously unrecognized binding pocket that could accommodate these otherwise anomalous regions of structure.

NMR and molecular orbital studies of isomerism and tautomerism in oximes of 2-acyl cyclic 1,3-diones.

Molecular orbital calculations and 13C and 15N NMR experiments have been performed on the O-methyl oximes of two types of 2-acyl cyclic 1,3-diones. One (III; X = CH2) was based on cyclohexane, and the other (X = O) on pyran. The data indicate that both the cyclohexane and pyran compounds prefer to exist as the oxime, rather than the enamine isomer. Two equivalent, interconverting, keto-enol tautomers exist in the cyclohexane compound. The pyran compound exists as the lactone-enol tautomer. Our results have implications in the design of herbicidal compounds and drugs containing similar tautomeric systems.