|
OALib Journal期刊
ISSN: 2333-9721
费用：99美元
|
|
|
|
基于药效团模型的乙酰胆碱酯酶、聚腺苷二磷酸核糖聚合酶-1双靶点分子设计研究
, PP. 819-823
Keywords: 药效团模型,药物设计,多靶点药物,ache抑制剂,parp-1抑制剂
Abstract:
本研究建立了乙酰胆碱酯酶（ache）和聚腺苷二磷酸核糖聚合酶-1（parp-1）抑制剂的药效团模型，设计、筛选了双靶点活性分子，并验证了其抑制活性，探讨了多靶点分子的设计策略。利用catalyst计算机辅助药物设计软件系统，以叠合程度和构象能进行筛选，得到具有ache、parp-1抑制活性的双靶点结构。通过计算机预测目标分子的理化性质，得到5个优选的氨基噻唑类衍生物。将匹配的优选化合物合成后进行对ache和parp-1的抑制活性的实验验证。其中化合物3对ache的抑制活性ic50为（0.337±0.052）μmol·l-1，而在1μmol·l-1浓度下对parp-1的抑制率为24.6%。证明药效团模型在多靶点药物设计和筛选中能起到减少盲目性和加快设计开发的作用。
| [1] | hopkinsal.networkpharmacology:thenextparadigmindrugdiscovery[j].natchembiol,2008,4:682-690.
|
| [2] | cavallia,bolognesiml,minarinia,etal.multi-target-directedligandstocombatneurodegenerativediseases[j].jmedchem,2008,51:347-372.
|
| [3] | morphyr,rankovicz.designedmultipleligands.anemergingdrugdiscoveryparadigm[j].jmedchem,2005,48:6523-6543.
|
| [4] | youdimmbh,buccafuscojj.multi-functionaldrugsforvariouscnstargetsinthetreatmentofneurodegenerativedisorders[j].trendspharmacolsci,2005,26:27-35.
|
| [5] | jenwitheesuke,horstja,rivaskl,etal.novelparadigmsfordrugdiscovery:computationalmultitargetscreening[j].trendspharmacolsci,2008,29:62-71.
|
| [6] | lenzsérg,kisb,snipesja,etal.contributionofpoly(adp-ribose)polymerasetopostischemicblood-brainbarrierdamageinrats[j].jcerebrbloodflowmetab,2007,27:1318-1326.
|
| [7] | kauppinentm,suhsw,bermanae,etal.inhibitionofpoly(adp-ribose)polymerasesuppressesinflammationandpromotesrecoveryafterischemicinjury[j].jcerebrbloodflowmetab,2009,29:820-829.
|
| [8] | gunerof.pharmacophoremodelingindrugdesign:recentadvances[j].currcomputaideddrugdes,2011,7:158.
|
| [9] | yamaotsun,hironos.3d-pharmacophoreidentificationforkappa-opioidagonistsusingligand-baseddrug-designtechniques[j].topcurrchem,2011,299:277-307.
|
| [10] | zhangsl,weiyx,liq,etal.pharmacophore-baseddrugdesignandbiologicalevaluationofnovelabcb1inhibitors[j].chembioldrugdes,2013,81:349-358.
|
| [11] | zhangwt,yanh,jiangfc.constructionofpharmacophoremodelofparp-1inhibitor[j].actapharmsin(药学学报),2007,42:279-285.
|
| [12] | zhuy,tongxy,zhaoy,etal.constructionofthepharmacophoremodelofacetylcholinesteraseinhibitor[j].actapharmsin(药学学报),2008,43:267-276.
|
| [13] | zhangwt,ruanjl,wupf,etal.design,synthesis,andcytoprotectiveeffectof2-aminothiazoleanaloguesaspotentpoly(adp-ribose)polymerase-1inhibitors[j].jmedchem,2009,52:718-725.
|
| [14] | rizzos,rivierec,piazzil,etal.benzofuran-basedhybridcompoundsfortheinhibitionofcholinesteraseactivity,betaamyloidaggregation,andabetaneurotoxicity[j].jmedchem,2008,51:2883-2886.
|
| [15] | piazzil,cavallia,bellutif,etal.extensivesarandcomputationalstudiesof3-{4-[(benzylmethylamino)methyl]phenyl}-6,7-dimethoxy-2h-2-chromenone(ap2238)derivatives[j].jmedchem,2007,50:4250-4254.
|
| [16] | bolognesiml,banzir,bartolinim,etal.novelclassofquinone-bearingpolyaminesasmulti-target-directedligandstocombatalzheimer'sdisease[j].jmedchem,2007,50:4882-4897.
|
| [17] | cecchellir,berezowskiv,lundquists,etal.modellingoftheblood-brainbarrierindrugdiscoveryanddevelopment[j].natrevdrugdiscov,2007,6:650-661.
|
| [18] | wagertt,houx,verhoestpr,etal.movingbeyondrules:thedevelopmentofacentralnervoussystemmultiparameteroptimization(cnsmpo)approachtoenablealignmentofdruglikeproperties[j].acschemneurosci,2010,1:435-449.
|
| [19] | ellmangl,courtneykd,andresvjr,etal.anewandrapidcolorimetricdeterminationofacetylcholinesteraseactivity[j].biochempharmacol,1961,7:88-95.
|
| [20] | csermelyp,agostonv,pongors.theefficiencyofmulti-targetdrugs:thenetworkapproachmighthelpdrugdesign[j].trendspharmacolsci,2005,26:178-182.
|
| [21] | chanky,wangw,wujj,etal.epidemiologyofalzheimer'sdiseaseandotherformsofdementiainchina,1990-2010:asystematicreviewandanalysis[j].lancet,2013,381:2016-2023.
|
| [22] | erkinjunttit,romang,gauthiers,etal.emergingtherapiesforvasculardementiaandvascularcognitiveimpairment[j].stroke,2004,35:1010-1017.
|
| [23] | baskysa,houac.vasculardementia:pharmacologicaltreatmentapproachesandperspectives[j].clinintervaging,2007,2:327-335.
|
| [24] | romangc,salloways,blackse,etal.randomized,placebo-controlled,clinicaltrialofdonepezilinvasculardementiadifferentialeffectsbyhippocampalsize[j].stroke,2010,41:1213-1221.
|
| [25] | strosznajderrp,czubowiczk,jeskoh,etal.poly(adp-ribose)metabolisminbrainanditsroleinischemiapathology[j].molneurobiol2010,41:187-196.
|
| [26] | alanocc,garnierp,yingwh,etal.nad(+)depletionisnecessaryandsufficientforpoly(adp-ribose)polymerase-1-mediatedneuronaldeath[j].jneurosci,2010,30:2967-2978.
|
| [27] | wangsp,xingzl,voslerps,etal.cellularnadreplenishmentconfersmarkedneuroprotectionagainstischemiccelldeath-roleofenhanceddnarepair[j].stroke,2008,39:2587-2595.
|
| [28] | tangks,suhsw,alanocc,etal.astrocyticpoly(adp-ribose)polymerase-1activationleadstobioenergeticdepletionandinhibitionofglutamateuptakecapacity[j].glia,2010,58:446-457.
|
Full-Text
|
|
Contact Us
service@oalib.com QQ:3279437679 
WhatsApp +8615387084133
|
|
