A Comprehensive Molecular Modeling Study of Phenyltriazolinone Derivatives as Protoporphyrinogen Oxidase (PPO) Inhibitors

ABSTRACT Herbicides that inhibit protoporphyrinogen IX oxidase (PPO) constitute an important class of highly effective agrochemicals with broad applications. In this work, an integrated computational strategy was employed to investigate the PPO inhibitory activity of a series of phenyltriazolinone herbicides containing five‐membered heterocyclic rings. The approach combined quantitative structure–activity relationship (QSAR) modeling, molecular docking, molecular dynamics simulations, and Poisson–Boltzmann surface area (PBSA) calculations. Recently synthesized compounds from this class were designed to modify the chemical structures of known PPO inhibitors and enhance their herbicidal performance. QSAR modeling of the available bioactivity data enabled the proposal of new derivatives, among which compound P7 exhibited a predicted pIC 50 value of 7.11. Two additional candidates, P4 and P5 , were also predicted to display higher herbicidal activity than the reference compound sulfentrazone. These findings were further supported by molecular docking and molecular dynamics analyses, which confirmed favorable binding modes and stable interactions with the PPO enzyme. Binding affinities were additionally evaluated through Gibbs free energy calculations using the PBSA method. Finally, feasible synthetic routes were proposed for the most promising compounds, supporting their potential development as next‐generation PPO inhibitors.