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 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, 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, we 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 5-LOX inhibitor was used, the flux of the COX-2 pathway was increased significantly, showing that 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 shutoff. We have also investigated the differences between a dual functional COX-2 and 5-LOX inhibitor and the mixture of these two types of inhibitors. Our work provides an example for the integration of systems biology and drug discovery.