Comparative ADMET, Docking and Molecular Dynamics Investigation of Novel Urea Scaffolds and Mesotrione for Sustainable Herbicide Development

The upward dominance of herbicide-resistant weeds has intensified the search for new herbicidal agents with improved efficacy, selectivity and environmental compatibility. In this study, a series of substituted urea derivatives were designed and computationally evaluated as potential inhibitors of 4-hydroxyphenylpyruvate dioxygenase (HPPD), a key enzymatic target in weed management. Molecular docking exploration discovered that several of the designated compounds unveiled resilient binding attraction toward the HPPD active points than the commercial herbicide Mesotrione. Among the evaluated derivatives, Compound -2 demonstrated the maximum satisfactory interaction contour with a MolDock score of -166.256Kcal/mol, significantly outperforming Mesotrione (-118.689Kcal/mol). The enhanced binding enactment of the nominated compounds was attributed to promising hydrogen bonding, hydrophobic interactions, aromatic stacking and van der Waals associations indoors of the catalytic central point. In addition, physicochemical, ADMET and radar plot analyses indicated that the majority of the derivatives possessed acceptable agrochemical properties, including balanced lipophilicity, suitable molecular size, moderate solubility and favorable permeability characteristics. Toxicity predictions further suggested improved safety profiles for the selected compounds, with no major indications of carcinogenicity, mutagenicity, skin sensitization, respiratory failure, or eye irritation. To further validate the stability of the ligand-protein systems, molecular dynamics simulations remained accomplished over a 100ns trajectory. The simulation findings demonstrated that Compound -2 maintained superior conformational stability and stronger interaction persistence within the HPPD active site compared with Mesotrione. This was evidenced by lower RMSD and RMSF fluctuations, stable solvent accessibility of surface area (SASA), consistent radius of gyration (Rg) values, and sustained hydrogen bond interactions through the simulation period. In contrast, the Mesotrione complex exhibited greater structural fluctuations and weaker dynamic stability. Collectively, the integrated docking, ADMET, toxicity and molecular dynamics results identify Compound -2 as a promising lead scaffold with enhanced inhibitory potential, favorable physicochemical behavior, improved predicted safety and strong structural stability. These findings support the potential application of substituted urea derivatives as next-generation HPPD-targeting herbicidal candidates for sustainable weed management strategies.Bottom of Form