Dynamic simulations on the Arachidonic Acid Metabolic Network

Abstract

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 antiinflammatory 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.

Computational Lipidomics and Lipid Bioinformatics: Filling In the Blanks

“…A rather general method for kinetic modeling of biochemical networks has been proposed by Rao et al [80]. A model for arachidonic acid metabolism in human polymorphic leukocytes based on ordinary differential equations (ODEs) has been developed by Yang et al [81]. This model elucidated flux changes upon drug treatment and provided information for drug discovery.…”

Target Identification and Validation of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate, an Anti-Inflammatory Natural Product

“…In contrast, no decrease in the PGE 21e vel. To further understand the pharmacologic effects of HOEC on the AA metabolic network, the dynamic propertie s of the AA metabolic network were studied using an established mathematical model (23)(24). The current study focused on five enzymes and six metabolites based on their biological significance.…”

Integration of Reaction Kinetics Theory and Gene Expression Programming to Infer Reaction Mechanism

“…The technology also permits verification against experimental results. Ideally, the resulting model may be used to predict progression of the disease (Bogojeska et al 2010, Burg et al 2009, Castiglione and Paci 2010, Degon et al 2008, de Sousa et al 2010, Guedj et al 2010, Hoffmann et al 2002, Itakura 2010, Perelson et al 1996, Smith and Ribeiro 2010, Srivastava et al 2002, von Kleist et al 2010, Wendelsdorf et al 2010, Yang et al 2007. It is also possible to identify, develop, and optimize treatment strategies in a mathematically rigorous fashion.…”