p糖蛋白抑制剂和底物的理论预测分析-theoretical prediction and analysis of p glycoprotein inhibitors and substrates.docxVIP

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p糖蛋白抑制剂和底物的理论预测分析-theoretical prediction and analysis of p glycoprotein inhibitors and substrates.docx

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p糖蛋白抑制剂和底物的理论预测分析-theoretical prediction and analysis of p glycoprotein inhibitors and substrates

TheoreticalstudiesonthepredictionsofP-glycoproteininhibitorsandsubstratesAbstractTheoreticalstudiesonthepredictionsofP-glycoproteininhibitorsandsubstratesAbstractATP-bindingcassette(ABC)transporterproteinfamilyisalargeclassoftransmembraneproteins,whichareexpressedinmanyorgans.ABCtransporterproteinprotectsthecellsfromtoxicsubstancesbypumpingthetoxicsubstancesoutofthecellswiththeenergyprovidedbyATP.P-glycoprotein(P-gp)isthemostrepresentativememberoftheABCtransporterproteinssuperfamily.P-gpisapseudo-symmetricalheterodimerwitheachmonomerconsistingoftwobundlesofsixtransmembrane(TM)andtwonucleotide-bindingdomains(NBDs).ThebindingpocketsofP-gparemainlylocatedattheTMareas.ThefunctionofNBDistobindATP,thusprovidingenergyforP-gpsubstratebinding.ItisreportedthatP-gpcantransportmanychemicallyandstructurallyunrelateddrugsandagents,resultingintheMDRphenomenonthataccountsforchemotherapeuticfailureinthetreatmentofcancers.besides,P-gpishighlyinvolvedinabsorption,distribution,metabolismandelimination(ADME)ofdrugs.Thus,researchesonP-gpinhibitorsandsubstrateshaveimportantsignificanceforcancertreatment.Thethesisisdividedintotwoparts.Inthefirstpart,wefirstlyreportedanextensivedatabaseof1273moleculesthatarecategorizedintoP-gpinhibitorsandnon-inhibitors.TheimpactofeightimportantphysicochemicalpropertiesonP-gpinhibitionwasexamined.Then,thedecisiontreeswerebuiltfromatrainingsetof973compoundsusingtherecursivepartitioning(RP)techniqueandvalidatedbyatestsetof300compounds.Thebestdecisiontreecorrectlypredicted83.5%oftheinhibitorsand67.0%ofthenon-inhibitorsinthetestset.Finally,na?veBayesiancategorizationmodelingwasappliedtoestablishclassifiersforP-gpinhibitors.TheBayesianclassifiergaveaveragecorrectpredictionfor81.7%of973compoundsinthetrainingsetusingaleave-one-outcross-validationprocedureand81.2%of300compoundsinthetestset.Wefoundthattheinclusionofmolecularfingerprintscouldimprovethepredictionsignificantly.Moreover,asanunsupervisedlearnerwithouttuningparameters,theAbstractTheoreticalstudiesonthepre