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Title: Insight into the structural requirements of protoporphyrinogen oxidase inhibitors: molecular modeling and CoMFA of diphenyl ether, isoxazole phenyl, and pyrazole phenyl ether

Author
item YANG, SHENG-GANG - Central China Normal University
item HAO, GE-FEI - Central China Normal University
item Dayan, Franck
item TRANEL, PATRICK - University Of Illinois
item YANG, GUANG-FU - Central China Normal University

Submitted to: Chinese Journal of Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/18/2013
Publication Date: 9/16/2013
Citation: Yang, S., Hao, G., Dayan, F.E., Tranel, P.J., Yang, G. 2013. Insight into the structural requirements of protoporphyrinogen oxidase inhibitors: molecular modeling and CoMFA of diphenyl ether, isoxazole phenyl, and pyrazole phenyl ether. Chinese Journal of Chemistry. 31:1153-1158.

Interpretive Summary: Protoporphyrinogen oxidase is an important targets for certain herbicides. The protein was expressed in vitro and several of those herbicides was tested to measure their effect on the enzyme activity. The data was then analyzed to determine the relationship between the herbicides structure and their respective activity. This study provides a new insight into the structural characteristics for the binding of the herbicides.

Technical Abstract: Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is one of the most significant targets for a large family of inhibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat cancer through photodynamic therapy (PDT). Molecular modeling and CoMFA were combined in a multistep framework with the ultimate goal of identifying important factor contributing to the activity of PPO inhibitors. As a continuation of the previous research work on the development of new PPO inhibitors, the bioassay results indicated that good PPO inhibitors were discovered in all of the three chemical series with I50 values ranging from 0.010 to 0.061 µM. Using the crystal structure of mtPPO as template, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment, leading to the development of a significant CoMFA model with r2 value of 0.98 and q2 (cross validation r2) value of 0.63. This novel multistep framework gives insight into the structural characteristics for the binding of inhibitors, and it can be extended to other classes of PPO inhibitors. In addition, the simplicity of the proposed approach may be particularly applicable in virtual screening procedures.