Predicting P-Glycoprotein-Mediated Drug Transport Based On Support Vector Machine and Three-Dimensional Crystal Structure of P-glycoprotein 英文参考文献.docVIP

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Predicting P-Glycoprotein-Mediated Drug Transport Based On Support Vector Machine and Three-Dimensional Crystal Structure of P-glycoprotein 英文参考文献.doc

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Predicting P-Glycoprotein-Mediated Drug Transport Based On Support Vector Machine and Three-Dimensional Crystal Structure of P-glycoprotein 英文参考文献

PredictingP-Glycoprotein-MediatedDrugTransport BasedOnSupportVectorMachineandThree- DimensionalCrystalStructureofP-glycoprotein ZsoltBikadi1,IstvanHazai1,DavidMalik1,KatalinJemnitz2,ZsuzsaVeres2,PeterHari3,ZhanglinNi5, TipW.Loo4,DavidM.Clarke4,EszterHazai1,QingchengMao5* 1Virtua Drug Ltd., Budapest, Hungary, 2Chemical Research Center, Hungary Academy of Sciences, Budapest, Hungary, 3Delta Services Ltd., Budapest, Hungary, 4Department of Medicine, Department and Biochemistry, University of Toronto, Toronto, Ontario, Canada, 5Department of Pharmaceutics, School of Pharmacy, UniversityofWashington,Seattle,Washington,UnitedStatesofAmerica Abstract HumanP-glycoprotein(P-gp)isanATP-bindingcassettemultidrugtransporterthatconfersresistancetoawiderangeof chemotherapeuticagentsincancercellsbyactiveeffluxofthedrugsfromcells.P-gpalsoplaysakeyroleinlimitingoral absorption and brain penetration and in facilitating biliary and renal elimination of structurally diverse drugs. Thus, identification of drugs or new molecular entities to be P-gp substrates is of vital importance for predicting the pharmacokinetics,efficacy,safety,ortissuelevelsofdrugsordrugcandidates.Atpresent,publiclyavailable,reliableinsilico models predicting P-gp substrates are scarce. In this study, a support vector machine (SVM) method was developed to predictP-gpsubstratesandP-gp-substrateinteractions,basedonatrainingdatasetof197knownP-gpsubstratesandnon- substratescollectedfromtheliterature.WeshowedthattheSVMmethodhadapredictionaccuracyofapproximately80% onanindependentexternalvalidationdatasetof32compounds.AhomologymodelofhumanP-gpbasedontheX-ray structureofmouseP-gpasatemplatehasbeenconstructed.WeshowedthatmoleculardockingtotheP-gpstructures successfully predicted thegeometry of P-gp-ligandcomplexes. Our SVMpredictionand themoleculardocking methods havebeenintegratedintoafreewebserver(),whichallowstheuserstopredictwhetheragiven compound is a P-gp substrate and how it binds to and interacts with P-gp. Utilizat