Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein 英文参考文献.docVIP

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Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein 英文参考文献.doc

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Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein 英文参考文献

ExhaustiveSamplingofDockingPosesRevealsBinding HypothesesforPropafenoneTypeInhibitorsof P-Glycoprotein FreyaKlepsch1,PeterChiba2,GerhardF.Ecker1* 1DepartmentofMedicinalChemistry,UniversityofVienna,Vienna,Austria,2InstituteofMedicalChemistry,MedicalUniversityofVienna,Vienna,Austria Abstract Overexpression of the xenotoxin transporter P-glycoprotein (P-gp) represents one major reason for the development of multidrug resistance (MDR), leading to the failure of antibiotic and cancer therapies. Inhibitors of P-gp have thus been advocated as promising candidates for overcoming the problem of MDR. However, due to lack of a high-resolution structuretheconcretemodeofinteractionofbothsubstratesandinhibitorsisstillnotknown.Therefore,structure-based designstudieshavetorelyonproteinhomologymodels.Inordertoidentifybindinghypothesesforpropafenone-typeP- gpinhibitors,fivedifferentpropafenonederivativeswithknownstructure-activityrelationship(SAR)patternweredocked into homology models of the apo and the nucleotide-bound conformation of the transporter. To circumvent the uncertainty of scoring functions, we exhaustively sampled the pose space and analyzed the poses by combining informationretrievedfromSARstudieswithcommonscaffoldclustering.Theresultssuggestpropafenonebindingatthe transmembranehelices5,6,7and8inbothmodels,withtheaminoacidresidueY307playingacrucialrole.Theidentified binding site in the non-energized state is overlapping with, but not identical to, known binding areas of cyclic P-gp inhibitorsandverapamil.Thesefindingssupporttheideaofseveralsmallbindingsitesformingonelargebindingcavity. Furthermore, the binding hypotheses for both catalytic states were analyzed and showed only small differences in their protein-ligandinteractionfingerprints,whichindicatesonlysmallmovementsoftheligandduringthecatalyticcycle. Citation: Klepsch F, Chiba P, Ecker GF (2011) Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P- Glycoprotein.PLo