Docking and 3D QSAR studies of protoporphyrinogen oxidase inhibitor 3H-pyrazolo[3,4-d][1,2,3]triazin-4-one derivatives.

Docking and three dimensional quantitative structure - activity relationship (3D-QSAR) studies have been performed for protoporphyrinogen oxidase (PPO) inhibitor 3H-pyrazolo[3,4-d][1,2,3]triazin-4-one analogues which are potential herbicides to protect agricultural products from unwanted weeds. The 3D-QSAR studies have been carried out using shape, spatial, electronic and molecular field descriptors along with a few structural parameters. The chemometric tools used for the analyses are genetic function approximation (GFA), partial least squares (PLS) and genetic partial least squares (G/PLS). The whole data set (n = 34) was divided into a training set (75% of the data set) and a test set (remaining 25%) on the basis of K-means clustering technique applied on topological, spatial and electronic descriptor matrix. Models developed from the training set were used to predict the activity of the test set compounds. All the models have been validated internally, externally and by Y-randomization technique. Docking studies suggest that the molecules bind with a hydrophobic pocket of the enzyme formed by some nonpolar amino acid (Ile168, Ile311, Ile412, Met365, Phe65 and Val164) residues. The QSAR studies suggest that for better activity the molecules should have symmetrical shape in the 3D space. For better PPO inhibitory activity, there should be a balance between the electrophilic and nucleophilic characters of the inhibitors. The charged surface area descriptors suggest that, the positive charge distributed over a large surface area may enhance the activity. Molecular field probes reflect that increase in steric volume and positively charged surface area may enhance the herbicidal activity.