Docking and 3D-QSAR studies of acetohydroxy acid synthase inhibitor sulfonylurea derivatives

Docking and three dimensional quantitative-structure activity relationship (3D-QSAR) studies were performed on acetohydroxy acid synthase (AHAS) inhibitor sulfonylurea analogues with potential herbicidal activity. The 3D-QSAR studies were carried out using shape, spatial and electronic descriptors along with a few structural parameters. Genetic function approximation (GFA) was used as the chemometric tool for this analysis. The whole data set (n = 45) was divided into a training set (75% of the data set) and a test set (remaining 25%) on the basis of the K-means clustering technique on a standardised topological, physicochemical and structural descriptor matrix. Models developed from the training set were used to predict the activity of the test set compounds. All models were validated internally, externally and using the Y-randomisation technique. Docking studies suggested that the molecules bind within a pocket of the enzyme formed by some important amino acid residues (Met351, Asp375, Arg377, Gly509, Met570 and Val571). In QSAR studies, molecular shape analysis showed that bulky substitution at the R1 position may enhance AHAS inhibitory activity. Charged surface area descriptors suggested that negative charge distributed over a large surface area may enhance this activity. The hydrogen bond acceptor parameter supported the charged surface area descriptors and suggested that, for better activity, the number of electronegative atoms present in the molecule should be high. The spatial descriptors show that, for better activity, the molecules should possess a bulky substituent and a small substitution at the R2 and R3 positions, respectively.