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.

药物分子不仅会与特定靶点相互作用，还会改变相关生物网络的状态与功能。如何在系统层面开展药物设计并评估其功能，已成为实现高效低不良反应药物研发的核心问题。花生四烯酸（arachidonic acid, AA）代谢网络是一类生成炎症介质的生物网络，其中包括环氧合酶-2（cyclooxygenase-2, COX-2）在内的多种酶已被用作抗炎药物的靶点。然而，无论是已有百年历史的非甾体类抗炎药，还是近年被撤市的万络（Vioxx），均未能实现完全成功的抗炎治疗。为深入探索抗炎药物研发路径，研究者针对人类多形核白细胞内的花生四烯酸（AA）代谢网络的动态特性展开了研究。研究采用常微分方程对代谢通量、外源性AA的作用效果以及药物效力进行了分析。研究发现，AA代谢网络的通量平衡对于实现高效且安全的药物研发至关重要。仅使用5-脂氧合酶（5-lipoxygenase, 5-LOX）抑制剂时，COX-2通路的通量会显著升高，这表明单一功能抑制剂无法有效调控炎症介质的生成。当同时阻断COX-2与5-LOX时，炎症介质的生成可被完全抑制。研究者还对比了双功能COX-2/5-LOX抑制剂与两类抑制剂联合使用的效果差异。该研究为系统生物学与药物研发的交叉融合提供了实践范例。