Dynamic Simulations on the Arachidonic Acid Metabolic Network 英文参考文献.docVIP

DynamicSimulationsontheArachidonicAcid MetabolicNetwork Kun Yang1,2,Wenzhe Ma1,2,Huanhuan Liang1,QiOuyang2,Chao Tang2,Luhua Lai1,2* 1Beijing National Laboratory for Molecular Sciences,State Key Laboratory for Structural Chemistry of Unstable and Stable Species, CollegeofChemistry and Molecular Engineering,PekingUniversity,Beijing,China,2CenterforTheoreticalBiology,PekingUniversity,Beijing,China Drugmoleculesnotonlyinteractwithspecifictargets,butalsoalterthestateandfunctionoftheassociatedbiological network.Howtodesigndrugsandevaluatetheirfunctionsatthesystemslevelbecomesakeyissueinhighlyefficient andlow–side-effectdrugdesign.Thearachidonicacidmetabolicnetworkisthenetworkthatproducesinflammatory 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-inflammatorydrugdesign,theauthorshavestudiedthedynamicpropertiesofarachidonicacid(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 mediatorscouldbecompletelyshutoff.Theauthorshavealsoinvestigatedthedifferencesbetweenadual-functional COX-2 and 5-LOX inhibitor and a mixture of these two types of inhibitors. Their work provides an example for the integrationofsystemsbiologyanddrugdiscovery. Citation:YangK,MaW,LiangH,OuyangQ,TangC,etal.(2007