Computational Innovation of Novel Tetrazolium- Nicotinamide Derivatives as HPPD Inhibitors for Next- Generation Herbicides

Abstract The escalating challenge posed by herbicide-resistant weed populations has intensified the search for new herbicidal agents with enhanced performance and distinct mechanisms of action. The reticence of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme in plant tyrosine degradation and carotenoid biosynthesis, remains an effective strategy for disrupting photosynthesis and causing plant lethality. In the contemporary work, a comprehensive computer coupling approach was employed to design and optimize tetrazolium nicotinamide-derived HPPD inhibitors using the 1TFZ crystal structure. This approach integrated 2D-QSAR analysis, molecular docking, structure-guided molecular modification, agrochemical-oriented ADMET evaluation, and molecular dynamics (MD) simulations. A reliable MLR-GFA QSAR model was established, demonstrating strong statistical robustness and acceptable predictive capability. Docking studies identified compounds 25-28 as potential HPPD inhibitors, with compound-26 displaying the most favorable binding affinity and a stable interaction pattern characterized by hydrogen bonding, halogen contacts, and aromatic interactions within the enzyme active site. Based on QSAR insights and binding-site interactions, focused modification at the -CF₃ substituent generated five new analogues (26a, 26b, 26c, 26d and 26e), four of which exhibited improved predicted herbicidal activity and enhanced binding behavior compared with the original scaffold. These modifications were attributed to improved electronic properties and better steric accommodation within the catalytic pocket. The evaluation of agrochemical-portrait and ADMET-related parameters indicated that, the premeditated compounds offer improved physicochemical profiles, environmental compatibility, and plant-specific safety compared to the commercial HPPD inhibitor mesotrione, with compound-26 emerging as the most promising candidate. In addition, a performance of 100 ns MD simulations verified the stability of the HPPD- compound-26 complex, as shown by consistent structural parameters, reduced flexibility, stable solvent exposure, and persistent hydrogen-bond formation. Following system equilibration, sustained hydrogen bonding highlighted the key stabilizing contributions of the tetrazolium and nicotinamide functional groups. In conclusion, compound-26 represents a strong structural template for next-generation HPPD-targeting herbicides, while -CF₃- position modification is confirmed as an operative approach for enlightening binding stability and predicted herbicidal efficacy. The study provides a solid computational framework to support future synthesis and experimental validation.