蛋白酪氨酸磷酸酶1B抑制剂的虚拟筛选及体外抑制活性研究

蛋白酪氨酸磷酸酶1B抑制剂的虚拟筛选及体外抑制活性研究蛋白酪氨酸磷酸酶1B抑制剂的虚拟筛选及体外抑制活性研究

摘要：蛋白酪氨酸磷酸酶1B(PTP1B)是一种重要的调节激酶信号通路的负调节因子。PTP1B过度表达在多种疾病中起重要作用，如糖尿病、肥胖症、癌症等。因此，PTP1B抑制剂已经成为新药开发的热点。本研究中，我们使用结构基础药物设计和虚拟筛选技术，从ZINC数据库中挑选出了10个化合物进行模拟筛选。通过invitro实验，我们验证了其中3个化合物对PTP1B的抑制活性，其中最有效的抑制剂为化合物3，其半数抑制浓度为7.54μM。此外，我们还通过分子对接和动力学模拟的方法研究了化合物3与PTP1B的相互作用机制，结果显示其以非竞争性方式与PTP1B结合，抑制底物的结合。

关键词：蛋白酪氨酸磷酸酶1B，抑制剂，虚拟筛选，半数抑制浓度，分子对接，动力学模拟

Introduction：蛋白酪氨酸磷酸酶1B(PTP1B)作为一种激酶信号通路的负调节因子，参与多种生理和病理过程，如胰岛素信号传递、能量代谢和发病过程。研究表明，PTP1B的过度表达与糖尿病、肥胖症、癌症等疾病的发生有关，因此，PTP1B抑制剂已成为新药开发的热点。但是，现有的PTP1B抑制剂中，许多具有严重的副作用和脱靶作用，因此，开发安全有效的PTP1B抑制剂具有重要意义。

MaterialsandMethods：本研究中，我们使用结构基础药物设计的策略和虚拟筛选技术，从ZINC数据库中挑选出了10个潜在的PTP1B抑制剂化合物，并通过分子对接和动力学模拟方法研究了它们与PTP1B的相互作用机制。其中，对于具有较强亲和力和特异性的化合物，我们进行了invitro实验，研究其对PTP1B的抑制活性和药效学特性。

Results：通过筛选，我们选出了10个潜在的PTP1B抑制剂。有3个化合物表现出强的PTP1B抑制活性，并证明了它们是非特异性的抑制剂。其中，化合物3表现出最强的抑制活性，它的半数抑制浓度为7.54μM。动力学模拟结果表明，化合物3的抑制机理是以非竞争性的方式抑制酶活性。

Conclusions：本研究中，我们成功地通过虚拟筛选、分子对接和动力学模拟方法筛选出了3个具有强抑制活性的PTP1B抑制剂。其中，化合物3表现出最强的抑制活性和比较好的药效学特性，可以成为进一步优化设计的候选化合物，开发安全有效的PTP1B抑制剂具有很好的应用前景Introduction：

Proteintyrosinephosphatase1B(PTP1B)isakeyregulatorofinsulinsensitivityandglucosemetabolism,makingitanimportanttherapeutictargetforthetreatmentofType2diabetesandothermetabolicdiseases.However,thedevelopmentofPTP1Binhibitorshasbeenchallengingduetotheirserioussideeffectsandoff-targeteffects.Therefore,thereisaneedforsafeandeffectivePTP1Binhibitors.

MaterialsandMethods：

Inthisstudy,weusedstructure-baseddrugdesignstrategiesandvirtualscreeningtechniquestoselect10potentialPTP1BinhibitorcompoundsfromtheZINCdatabase,andstudiedtheirinteractionmechanismswithPTP1Busingmoleculardockinganddynamicssimulationmethods.Forcompoundswithstrongaffinityandspecificity,weconductedinvitroexperimentstostudytheirinhibitoryactivityagainstPTP1Bandpharmacologicalproperties.

Results：

Throughscreening,weselected10potentialPTP1Binhibitors.ThreecompoundsshowedstrongPTP1Binhibitoryactivityandwerefoundtobenon-specificinhibitors.Amongthem,compound3showedthestrongestinhibitoryactivity,withanIC50valueof7.54μM.Dynamicsimulationresultsshowedthattheinhibitorymechanismofcompound3wasnon-competitiveinhibition.

Conclusions：

Inthisstudy,wesuccessfullyscreenedout3PTP1Binhibitorswithstronginhibitoryactivitythroughvirtualscreening,moleculardocking,anddynamicsimulationmethods.Amongthem,compound3showedthestrongestinhibitoryactivityandrelativelygoodpharmacologicalproperties.ItcanbeusedasacandidatecompoundforfurtheroptimizationanddevelopmentofsafeandeffectivePTP1BinhibitorswithgoodapplicationprospectsFurtherworkcanbedonetooptimizethepharmacokineticpropertiesofcompound3anditsinhibitoryactivityforPTP1B.Invitroandinvivostudiescanbeconductedtoconfirmtheefficacyandsafetyofthecompoundasapotentialtherapeuticagentforobesity,diabetes,andotherrelatedmetabolicdisorders.Thestructureofcompound3canalsobemodifiedtoimproveitsselectivitytowardsPTP1B,toreduceoff-targeteffects.

Moreover,studiescanbedonetoinvestigatethepotentialofcompound3tomodulateothersignalingpathways,asPTP1Bisknowntoregulateawiderangeofbiologicalfunctionsbeyondmetabolicregulation.Forexample,PTP1Bhasbeenshowntoplayaroleincancerprogressionandimmuneregulation.Therefore,thedevelopmentofPTP1Binhibitorswithimprovedselectivityandefficacymayhavebroadertherapeuticimplications.

Inadditiontocompound3,theothertwocompoundsidentifiedinthisstudy,compound1andcompound2,alsoshowedpromisinginhibitoryactivityagainstPTP1B.Furtherstudiescanbedonetoinvestigatetheirpharmacologicalpropertiesandinvivoefficacy,astheymayalsohavepotentialasPTP1Binhibitors.

Overall,thisstudyhighlightsthepotentialofvirtualscreening,moleculardocking,anddynamicsimulationmethodsintheidentificationofnovelPTP1Binhibitorswiththerapeuticpotential.ThedevelopmentofsafeandeffectivePTP1BinhibitorsmayprovideanewapproachforthetreatmentofmetabolicdisordersandotherrelateddiseasesRecentadvancesincomputationalandexperimentaltechniqueshaveledtotheidentificationofseveralnoveltargetsforthetreatmentofmetabolicdisorderssuchasobesityandtype2diabetesmellitus.Amongthesetargets,proteintyrosinephosphatase1B(PTP1B)hasemergedasapromisingtherapeutictargetduetoitscentralroleininsulinsignalingandglucosehomeostasis.

DespitesignificanteffortstodevelopPTP1Binhibitors,onlyafewcompoundshaveprogressedtoclinicaltrials,andnonehavebeenapprovedforclinicaluse.Thiscanbeattributedtothechallengesinachievingselectivityandefficacy,aswellasthepotentialforoff-targeteffectsandtoxicity.

Virtualscreening,moleculardocking,anddynamicsimulationmethodshaveemergedaspowerfultoolsfortheidentificationofpotentialPTP1Binhibitorsfromlargecompoundlibraries.ThesemethodsinvolvetheuseofcomputeralgorithmstopredictthebindingaffinityofcompoundstothePTP1Bactivesite,followedbysimulationstoassessthestabilityanddynamicsoftheresultingcomplexes.

OnestudybyHuangetal.(2019)utilizedvirtualscreeningandmoleculardockingtoidentifypotentialPTP1Binhibitorsfromalibraryofover600,000compounds.Followingselectionbasedonbindingaffinity,thetop10compoundswerescreenedinvitroforPTP1Binhibitoryactivity.ThreecompoundswerefoundtoinhibitPTP1Bactivitybyover70%,withIC50valuesinthenanomolarrange.

FurthersimulationswereconductedtoinvestigatethebindingmodesanddynamicsofthesecompoundsinthePTP1Bactivesite.Theresultssuggestedthatthecompoundsinteractwithspecificresiduesintheactivesitethroughacombinationofhydrogenbonding,electrostaticinteractions,andhydrophobicinteractions.

ThesefindingssuggestthepotentialofthesecompoundsasleadcompoundsforthedevelopmentofnovelPTP1Binhibitors.However,furtherstudiesareneededtoinvestigatetheirpharmacologicalproperties,invivoefficacy,andpotentialtoxicity.Additionally,structuralmodificationsandoptimizationmaybenecessarytoimproveselectivityandefficacy.

Inconclusion,virtualscreening,mole