Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model 英文参考文献.docVIP

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Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model 英文参考文献.doc

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Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model 英文参考文献

DrugOff-TargetEffectsPredictedUsingStructural AnalysisintheContextofaMetabolicNetworkModel RogerL.Chang1,LiXie2,LeiXie3,PhilipE.Bourne2,3,Bernhard?.Palsson1* 1Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America, 2Skaggs School of Pharmacy and Pharmaceutical Sciences,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,3SanDiegoSupercomputerCenter,UniversityofCaliforniaSanDiego,LaJolla, California,UnitedStatesofAmerica Abstract Recentadvancesinstructuralbioinformaticshaveenabledthepredictionofprotein-drugoff-targetsbasedontheirligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbationsusinglarge-scalenetworkmodels.Integrationofthesetwocapabilitiesprovidesaframeworkforevaluating metabolicdrugresponsephenotypesinsilico.Thiscombinedapproachwasappliedtoinvestigatethehypertensiveside effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previouslybeenobservedtoimpactrenalfunctioningene-deficientpatientsandmayplayaroleintheadversesideeffects observedinclinicaltrials.Geneticriskfactorsfordrugtreatmentwerealsopredictedthatcorrespondtobothcharacterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implicationsfordrugdevelopmentandpersonalizedmedicine. Citation:ChangRL,XieL,XieL,BournePE,PalssonB?(2010)DrugOff-TargetEffectsPredictedUsingStructuralAnalysisintheContextofaMetabolicNetwork Model.PLoSComputBiol6(9):e1000938.doi:10.1371/journal.pcbi.100