Dynamic simulations on the arachidonic acid metabolic network.
Drug molecules not only interact with specific targets, but also alter the state and function of the associated biological network. How to design drugs and evaluate their functions at the systems level becomes a key issue in highly efficient and low-side-effect drug design. The arachidonic acid metabolic network is the network that produces inflammatory mediators, in which several enzymes, including cyclooxygenase-2 (COX-2), have been used as targets for anti-inflammatory drugs. However, neither the century-old nonsteriodal anti-inflammatory drugs nor the recently revocatory Vioxx have provided completely successful anti-inflammatory treatment. To gain more insights into the anti-inflammatory drug design, the authors have studied the dynamic properties of arachidonic acid (AA) metabolic network in human polymorphous leukocytes. Metabolic flux, exogenous AA effects, and drug efficacy have been analyzed using ordinary differential equations. The flux balance in the AA network was found to be important for efficient and safe drug design. When only the 5-lipoxygenase (5-LOX) inhibitor was used, the flux of the COX-2 pathway was increased significantly, showing that a single functional inhibitor cannot effectively control the production of inflammatory mediators. When both COX-2 and 5-LOX were blocked, the production of inflammatory mediators could be completely shut off. The authors have also investigated the differences between a dual-functional COX-2 and 5-LOX inhibitor and a mixture of these two types of inhibitors. Their work provides an example for the integration of systems biology and drug discovery.
Yang
Kun
K
Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Ma
Wenzhe
W
Liang
Huanhuan
H
Ouyang
Qi
Q
Tang
Chao
C
Lai
Luhua
L
D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D016718:Arachidonic Acid / Q000008:administration & dosage* / Q000378:metabolism*; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D018448:Models, Immunological; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D007155:Immunologic Factors; D016718:Arachidonic Acid