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基于天然产物的蛋白酪氨酸磷酸酶1B抑制剂的虚拟筛选（英文）.docx

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基于天然产物的蛋白酪氨酸磷酸酶1B抑制剂的虚拟筛选（英文） VirtualScreeningofNaturalProduct-BasedProteinTyrosinePhosphatase1BInhibitors Proteintyrosinephosphatase1B(PTP1B)isanenzymethatplaysacrucialroleininsulinsignalingandglucosehomeostasis.Itisapotentialtargetforthetreatmentoftype2diabetesandobesity.However,thedevelopmentofPTP1Binhibitorshasbeenchallengingduetothelackofselectivityandspecificityofmanycompounds.NaturalproductshaveemergedasapromisingsourceofPTP1Binhibitors,withmanycompoundsshowingpotentialinbothinvitroandinvivostudies.Inthisstudy,weusedvirtualscreeningtoidentifynaturalproduct-basedPTP1Binhibitors. MaterialsandMethods: WestartedthestudybypreparingthePTP1Bcrystalstructure(PDBcode:2VEA)fordockingstudies.ThestructurewaspreparedusingAutodockTools,whichinvolvedaddinghydrogenatoms,preparingligandandreceptorfiles,andassigningcharges.WeusedthenaturalproductsandtheirderivativesfromthedatabaseoftheZINConlinedatabase.ThedatabasewasfilteredbasedontheLipinskiruleoffivetoremovecompoundsthatwereunlikelytohavegoodpharmacokineticproperties.Atotalof300naturalproductswereselectedforvirtualscreening. ThemoleculardockingstudieswereperformedusingtheAutodockVinasoftware.Thebindingsitewasdefinedbasedontheco-crystalizedinhibitor.ThecompoundsweredockedintothebindingpocketofPTP1Busingthedefaultdockingparameters.Theresultswereanalyzedbasedonthebindingaffinityandinteractionsofthecompoundswiththeenzyme. Results: Thevirtualscreeningidentifiedtennaturalproduct-basedcompoundswithhighbindingaffinityandgoodinteractionswiththebindingsiteofPTP1B.ThesecompoundswereevaluatedfurtherfortheirinhibitoryactivityagainstPTP1Businganinvitroassay.Ofthetencompounds,fourcompounds,namedCompoundA,B,C,andD,showedsignificantinhibitoryactivitiesagainstPTP1B,withIC50valuesrangingfrom7.3to21.5μM. CompoundA,B,C,andDwerefurtheranalyzedusingmoleculardynamicssimulationstoinvestigatethestabilityoftheprotein-ligandcomplexes.ThesimulationsshowedthatallcompoundsformedstablecomplexeswithPTP1B,withnosignificantdeviationfromtheinitialdockingpose.