Binding mode of aryloxyphenoxypropionate (FOP) and cyclohexanedione (DIM) groups of herbicides at the carboxyl transferase (CT) domain of Acetyl-CoA carboxylase of Phalaris minor

Phalaris minor (P. minor) is a major weed of wheat crop. It has developed resistance as well as cross-resistance against aryloxyphenoxypropionates (FOP) and cyclohexanediones (DIM) group of herbicides, probably due to mutations in the binding site of acetyl-CoA carboxylase (ACCase) at its carboxyl transferase domain (CT-domain). Binding of FOP and DIM group of herbicides inhibits de novo synthesis of fatty acids, which is essential for survival of P. minor. This work highlights atomistic details of binding mode of diclofop (FOP) and tepraloxydim (DIM) groups of herbicides in the CT-domain of modelled P. minor ACCase protein. Molecules have been extracted from ZINC database based upon their 2D structural similarities with existing FOP and DIM groups of herbicides, which has been further screened at FOP- and DIM-binding sites of the modelled protein. Rigid and flexible docking has been performed to prioritise hits considering the diclofop and tepraloxydim as a reference. Finally, two molecules of the FOP group and three molecules of DIM group have been obtained that have shown better predicted binding affinity, ligand efficiency, and inhibition constant as compared to the reference molecules. Molecular dynamics simulation of about 10 ns was performed for both the reference molecules as well as for all the five prioritised molecules to determine their conformational stability and prominent H-bond network. Amino acid residues A56 and I160 of D1 protein are equivalent to A1705 and I1181 amino acids of black grass, as well as A1627 and I1735 amino acids of yeast (PDB ID: 1UYR) forms invariant hydrogen bond with reference and screened molecules. It was concluded that common binding features of FOP and DIM may be utilised for development of bitopic herbicide.