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Fluorinated benzoxazinones designed via MIA‐QSAR , docking and molecular dynamics as protoporphyrinogen IX oxidase inhibitors

Year: 2024
Type: article
Abstract: BACKGROUND Fluorine plays a significant role in agrochemical science because approximately 25% of herbicides licensed worldwide contain this element. In a pool of previously synthesized benzoxazinones, some compounds contained fluorine and demonstrated inhibitory activities against protoporphyrinogen IX oxidase (PPO). Therefore, three data sets of benzoxazinone derivatives with known inhibitory activity against PPO were employed to build a multivariate image analysis applied to a quantitative structure–activity relationships (MIA‐QSAR) model to identify improved analogs with at least one fluorine substituent. RESULTS The QSAR model was vigorously validated and demonstrated to be highly predictive (r2 = 0.85, q2 = 0.71, and r2pred = 0.88); thus, the model can provide reliable estimations for the PPO inhibitory activity of unknown derivatives. From these compounds, a couple of N‐substituted benzoxazinones that contained the ‐CH2CHF2 group were found with predicted pKi values larger than 8 (Ki in mol L−1) and higher lipophilicity than the most active data set compounds. In addition, we carried out a systematic investigation of the binding mode of PPO by performing computational docking followed by molecular dynamics simulations. The proposed binding mode was consistent with experimental studies, and several potential key residues were identified. CONCLUSION Two new proposed benzoxazinones exhibited better performance than compounds of the data set, and fluorine substituents played pivotal roles in describing the biological activities. © 2024 Society of Chemical Industry.
DOI: 10.1002/jsfa.13361
Language: English
Open Access status: bronze
OpenAlex ID: W4391611191
FWCI: 1.003
Cites: 39
Cited by: 5
Related to: 10