Journal of Computer-Aided Molecular Design

, Volume 25, Issue 3, pp 213–222 | Cite as

Structure–activity relationships of diphenyl-ether as protoporphyrinogen oxidase inhibitors: insights from computational simulations



Protoporphyrinogen oxidase (PPO, EC, which has been identified as a significant target for a great family of herbicides with diverse chemical structures, is the last common enzyme responsible for the seventh step in the biosynthetic pathway to heme and chlorophyll. Among the existing PPO inhibitors, diphenyl-ether is the first commercial family of PPO inhibitors and used as agriculture herbicides for decades. Most importantly, diphenyl-ether inhibitors have been found recently to possess the potential in Photodynamic therapy (PDT) to treat cancer. Herein, molecular dynamics simulations, approximate free energy calculations and hydrogen bond energy calculations were integrated together to uncover the structure–activity relationships of this type of PPO inhibitors. The calculated binding free energies are correlated very well with the values derived from the experimental k i data. According to the established computational models and the results of approximate free energy calculation, the substitution effects at different position were rationalized from the view of binding free energy. Some outlier (e.g. LS) in traditional QSAR study can also be explained reasonably. In addition, the hydrogen bond energy calculation and interaction analysis results indicated that the carbonyl oxygen on position-9 and the NO2 group at position-8 are both vital for the electrostatic interaction with Arg98, which made a great contribution to the binding free energy. These insights from computational simulations are not only helpful for understanding the molecular mechanism of PPO-inhibitor interactions, but also beneficial to the future rational design of novel promising PPO inhibitors.


Protoporphyrinogen oxidase Diphenyl-ether inhibitor Molecular dynamics simulations Structure–activity relationship 



Protoporphyrinogen oxidase


Photodynamic therapy


Structure activity relationship






Hydrogen bond energy



The research was supported in part by the National Basic Research Program of China (No. 2010CB126103), the NSFC (No. 20925206 and 20932005) and the PCSIRT (No. IRT0953).

Supplementary material

10822_2011_9412_MOESM1_ESM.doc (30 kb)
Supplementary material 1 (DOC 29 kb)


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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Ge-Fei Hao
    • 1
  • Ying Tan
    • 1
  • Ning-Xi Yu
    • 1
  • Guang-Fu Yang
    • 1
  1. 1.Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of ChemistryCentral China Normal UniversityWuhanPeople’s Republic of China

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