Quantitative Biology

, Volume 7, Issue 1, pp 30–41 | Cite as

Pharmacodynamics simulation of HOEC by a computational model of arachidonic acid metabolic network

  • Wen Yang
  • Xia Wang
  • Kenan Li
  • Yuanru Liu
  • Ying LiuEmail author
  • Rui WangEmail author
  • Honglin LiEmail author
Research Article



Arachidonic acid (AA) metabolic network is activated in the most inflammatory related diseases, and small-molecular drugs targeting AA network are increasingly available. However, side effects of above mentioned drugs have always been the biggest obstacle. (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a natural product acted as an inhibitor of 5-lipoxygenase (5-LOX) and 15-LOX in vitro, exhibited weaker therapeutic effect in high dose than that in low dose to collagen induced arthritis (CIA) rats. In this study, we tried to elucidate the potential regulatory mechanism by using quantitative pharmacology.


First, we generated an experimental data set by monitoring the dynamics of AA metabolites’ concentration in A23187 stimulated and different doses of HOEC co-incubated RAW264.7. Then we constructed a dynamic model of A23187-stimulated AA metabolic model to evaluate how a model-based simulation of AA metabolic data assists to find the most suitable treatment dose by predicting the pharmacodynamics of HOEC.


Compared to the experimental data, the model could simulate the inhibitory effect of HOEC on 5-LOX and 15-LOX, and reproduced the increase of the metabolic flux in the cyclooxygenase (COX) pathway. However, a concomitant, early-stage of stimulation-related decrease of prostaglandins (PGs) production in HOEC incubated RAW264.7 cells was not simulated in the model.


Using the model, we predict that higher dose of HOEC disrupts the flux balance in COX and LOX of the AA network, and increased COX flux can interfere the curative effects of LOX inhibitor on resolution of inflammation which is crucial for the efficient and safe drug design.


arachidonic acid metabolic network computational model anti-inflammation natural product 



The research is supported in part by the National Key Research and Development Program (No. 2016YFA0502304), Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase, No.U1501501), and the National Natural Science Foundation of China (No. 21173076). Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-notch Young Professionals.

Supplementary material

40484_2018_163_MOESM1_ESM.pdf (577 kb)
S1 Ordinary differential equations (ODEs) of in AA metabolic pathway


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Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Shanghai Key Laboratory of New Drug Design, School of PharmacyEast China University of Science and TechnologyShanghaiChina
  2. 2.BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular EngineeringPeking UniversityBeijingChina

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