[生物医药论文精品]血管紧张素ⅱat1受体拮抗剂药效团模型构建

血管紧张素AT1受体拮抗剂药效团模型构建摘要A1A0A2A3A4A5A6A8AT1A9A7A10A11A12A13A14A15A16A17A19A20A18CATALYSTA22A21A23A24A26A27A25A28A29A30A32A7A31A33A34A35A36A3782A39A38A40A41A42A43A44A45A46A40A26A48A47A49A44A50A26A44A45A51A52A53A54A55A47A56A57A13A14A15A16A17A26A58A59A60A39A61A291A39A62A63A64A9A7A262A39A65A66A67A68A261A39A69A70A45A67A68A521A39A71A72A73A74A15A37AT1A9A7A10A11A12A13A14A15A16A17A19A75A76A77A36A30A78A79RMS074,CORREL087,WEIGHT139,CONFIG2090A80A26A28A29A30A78A37A35A36A81A82A83A84A26A29A85A86A87A17A88A47A37AT1A9A7A10A11A12A37A89A90A19关键词A90A91A92A93A85A13A41A89A90A94A95A96A97A98A99A100AT1A9A7A10A11A12A94A13A14A15A16A17THECONSTRUCTIONOFTHEPHARMACOPHOREMODELOFTHEANGIOTENSINAT1RECEPTORANTAGONISTSABSTRACTTOCONSTRUCTTHEPHARMACOPHOREMODELOFTHEANGIOTENSINAT1RECEPTORANTAGONISTSTENPHARMACOPHOREMODELSOFAT1RECEPTORANTAGONISTSWEREESTABLISHEDFROMTHETRAININGOF82AT1RECEPTORANTAGONISTSWITHCONFORMERANALYSISANDPHARMACOPHOREMAPPINGBYUSINGTHECATALYSTSOFTWAREANOPTIMALPHARMACOPHOREMODELINCLUDINGONEHYDROGENBONDINGACCEPTOR,TWOHYDROPHOBICCORE,ONENEGATIVEIONIZABLEANDTWORINGAROMATICSWASCONFORMEDTHERELIABILITYOFTHEOPTIMALPHARMACOPHOREMODELISPREFERABLYWITHRMS074,CORREL087,WEIGHT139,ANDCONFIG209THISPHARMACOPHOREMODELSHOWEDEXCELLENTFORECASTABILITYANDCONTRIBUTESTODESIGNTHEAT1RECEPTORANTAGONISTSWITHUNDISCOVEREDSTRUCTUREKEYWORDSCADDANGIOTENSINAT1RECEPTORANTAGONISTSPHARMACOPHOREMODEL肾素血管紧张素醛固酮系统（RAAS）是参与心血管功能调节的重要内分泌系统，存在于机体各组织器官，在高血压的发生发展中起着至关重要的作用。血管紧张素原在循环或局部肾素作用下形成血管紧张素（ANG），ANG可被血管紧张素转化酶（ACE）在内皮细胞内转化为血管紧张素（ANG）A1011A102。而后一途径也可由组织蛋白酶G，心脏的糜蛋白酶，胰蛋白酶等非ACE途径而完成。ANG是RAAS的主要效应分子，在维护心血管自身稳定等方面起着重要的作用。非ACE途径决定了ACEI不能完全抑制ANG的产生，ANG的主要受体有AT1和AT2两种，研究表明ANG的主要生理药理作用是通过G蛋白偶联的AT1受体起作用的A1032A104，而且AT1拮抗剂无论ANGG7481G9316于ACE或是糜酶，G3355有效A1033A104。G3252G8504，G16786G16757AT1拮抗剂G8503成为G1166G1216研究的重G9869。药效G3254G8181G3423G8873是一种G7380G3835G19492G5242的G2045用G5062G11705分子的G989维G13479G7512G1461G5699G17839G15904药G10301分子G16786G16757的方G88734，G989维药效G3254G8181G3423是与一G1022化G2524G10301一定生G10301G8975G5627有关的G3282G16949G19610G2524，由表G5461分子生G10301G8975G5627的G13479G7512G10317G5461和G10301理G4658G5627组成，G4439应G2265G2559药G10301与受体G13479G2524G7114受体G13479G2524部G1313的一G1135G13479G7512G1461G5699，用G7481G6363G4560药G10301G2524成，且G2524成的药G10301应G16825G1867有一定的生G10301G8975G5627。G2045用药效G3254不G1177可G1209G4557G7044化G2524G10301G17839G15904G8975G5627G20056G8991，G17836可G1209G13479G2524G989维G13479G7512在G6980G6466G5223中G4559G6226G10317定G989维G13479G7512的分子，G6164G1209G7512G5326有效的药效G3254G8181G3423G4557于G7044药的G16786G16757是G2325分关G19202的。A105A106A107A108A109AT1拮抗剂主要是G1209G8943G8813G3386为G1820G4560G10301而G2524成的，G13479G7512G17751为G2345一。G3252G8504，G7424G7003G2045用G5062G6265G4560的血管紧张素AT1受体拮抗剂，G17885G6333在体G3818G4466G20576中G4557AT1受体拮抗G8975G5627G17751高的不G2528G13479G7512G12879G3423的82G1022化G2524G10301为G7691G7424，通过G16757G12651机G17753G2173药G10301G16786G16757，G6226G2052化G2524G10301G1861G2528的药效作用G8181G5347，G5647G13479G1998G4557G8975G5627至关重要的药效G10317G5461G1815素G2462G1866G12366G19400G6502G2027形G5347G2375药效G3254G8181G3423，G5194在G6980G6466G5223中G6640G4559G12538G2524G8504药效G3254G13479G7512G10317G5461的化G2524G10301，G5194G1209G1866为G1820G4560G10301G16786G16757G1998G1867有G7044G3423G13479G7512G10317G5461的血管紧张素AT1受体拮抗剂。1研究方法与内容ANGAT1受体拮抗剂药效G3254的研究G18331用了MSIG1856G2508的CATALYSTG17731G1226G2265，在SGIG3282形G5049作G12461G990完成，主要G8181G3371G2265G6336VIEWCOMPOUNDWORKBENCH,VIEWHYPOTHESISWORKBENCH,GENERATEHYPOTHESISWORKBENCH。药效G3254G16794G2047的G3534G7424G8505G20600G2265G6336G8975G5627化G2524G10301的G17885G6333，G7512G16949分G7524和药效G3254G8181G3423G7512G5326。活性化合物的选择为了G1363G6164G5326G12447的药效G3254G8181G3423G7368G1867有G1207表G5627，G7424G4466G20576G17885G2474了不G2528G7003G10498G6265G17959的G3822种G13479G7512G12879G3423的化G2524G10301，G1186中G17885G2474了在体G3818G4466G20576中G4557AT1受体G1867有G17751高抑制G8975G5627的82G1022化G2524G10301组成分子G19610G2524（表1），G6164有的化G2524G10301G3355满足IC501MOLL1，且G8975G5627相差在G989G1022G6980量级G1209内。在CATYALYST中的VIEWCOMPOUNDG8181G3371中G5326G12447化G2524G10301的G13479G7512，G5194G4557G1866二维和G989维G12366G19400G13479G7512G17839G15904优化，G2045用3DMINIMISE求G1998G1867有G7380低能量的G989维G12366G19400G7512G16949。TABLE1THESTRUCTUREANDCONFORMATIONNUMBEROFTHESELECTEDCOMPOUNDS15691017181921222330313238394042434546474850515354575859606364656667、6869、70717576808182THEDATAOFIC50FROMREF5COMPD15,6COMPD617,7COMPD1822,8COMPD2338,9COMPD39,10COMPD4050,11COMPD5163,12COMPD64,13COMPD6570,14COMPD7182,SEPARATELY化合物的构象分析药G10301在与G1866靶G9869发生相互作用G7114，为了能产生好的几何匹配和能量匹配，会G18331G2474G10317定的G7512G16949G8181G5347，G2375G8975G5627G7512G16949，G4439G2375G1363不是G7380低能量的G7512G16949，也通常是能量G17751低的G7512G16949。在CATALYSTG17731G1226G2265里，给G1998了G7512G16949分G7524的一G1022经G20576G5627的能量截断缺省值84KJMOL1。也就是说当药G10301分子与受体发生相互作用G7114，分子的G8975G5627G13479G7512和能量G7380低G7512G16949比G17751，G1866差值可在084KJMOL1之G19400变化，为了适应受体G13479G7512的变化，84KJMOL1G1209内的低能分子G7512G16949都可能与受体G13479G2524。G18331用BESTQUANLITYG8181G5347，将G7380G3835G7512G16949G6980目G16786定为255G1022，G4557G6164G7512G5326的化G2524G10301分子G17839G15904处理，生成了一系G2027低能G7512G16949，经G7512G16949分G7524之后，每G1022G8975G5627分子都可G1209得G2052一组与G1866能量相G4557应的低能G7512G16949，表1中G2027G1998了经G7512G16949分G7524后得G2052的化G2524G10301G7512G16949G6980。药效团模型的构建G2045用VIEWHYPOTHESISWORKBENCHG8181G3371G6640G4559G6164G17885的化G2524G10301的药效G3534G3254G1815素。根G6466药效G3534G3254G1815素分G7524的G13479果，G17885G6333氢G19202接受体（HBA），氢G19202供体（HBD），疏水中心（HP），环芳香G5627（RA）和阴离子中心（NI）5G1022药效G3534G3254G8181G3423参G6980。将G17885定的化G2524G10301G4560入GENERATEHYPOTHESISWORKBENCH，G5194输入G1866G8975G5627值，考虑G2052G7424G7003G6164G17885G2474的化G2524G10301分子的G8975G5627G6980G6466G7481自于不G2528作者的G3822组G4466G20576，G2528G7114G8975G5627检G8991都可能存在一定的误差。G3252G8504将G8975G5627G6980G6466的不确定G5242（ACTIVITYUNCERTAINTY）G16786置为30。由CATALYST中的GENERATEHYPOTHESISWORKBENCH命令生成药效G3254G8181G3423。G16786定生成的药效G3254G8181G3423G6164G2559有的药效G1815素（N）范围为1N10。在产生药效G3254的过程中G18331用了CATALYST中参G6980的缺省G16786置。将G6164有参G6980G16786定完后，通过CATALYST中的CATHYPO命令G16794G2047G5194确定药效G3254。G2045用GENERATEHYPOTHESISG8181G3371，G16757G12651G13479果给G1998了10G1022得分G7380高的药效G3254G8181G3423G2462相应的统G16757评价得分。2结果与讨论G2045用层次聚G12879分G7524方G8873，按照药效G3254G12366G19400相似G5627评价将10G1022药效G3254G8181G3423分为四G12879G1866中药效G3254G8181G34231，2为第一G12879，3，6，7为第二G12879，4，5为第G989G12879，8，9，10为第四G12879。G1186G8181G3423的统G16757评价G7481看，第一G12879中的药效G3254G8181G3423比G1866他的G1867有G7368好的G20056G8991能力。G1866中G1867有G17751好的相关系G6980和权重G5242（RMS074,CORREL087,WEIGHT139,CONFIG2090）的G8181G3423一是G7380佳药效G3254G8181G3423（G32821）。将化G2524G103015与药效G3254G8181G3423G17839G15904叠和（G32822），G13479果非常匹配（FIT874,G20056G8991值031NMOLL1，G4466G8991值047NMOLL1）。FIGURE1THEOPTIMALPHARMACOPHOREMODELG7380佳的药效G3254G8181G3423G2265G63361G1022氢G19202接受体，2G1022疏水中心，1G1022阴离子中心和1G1022环芳香G3534G3254，而且各药效G3534G3254G3355满足一定的G12366G19400G19492制。（G2375各药效G3254之G19400的距离A5365NM,B7436NM,C8938NM,D7700NM,E4748NM,F12141NM,G7580NM,H6312NM,I7029NM）表明G16825G12879化G2524G10301在与AT1受体发生G16794G2047G7114，主要存在四G12879G17751强的相互作用，G2375氢G19202相互作用，疏水G19202相互作用，环芳香G5627作用和阴离子的作用。FIGURE2MAPPINGOFTHECOMPOUND5ONTOTHEOPTIMALPHARMACOPHOREMODEL根G6466化G2524G10301G19610G6980G6466G5326G12447的G13479G7512G8975G5627关系，CATALYST通过G6164G17885G6333的化G2524G10301的G8975G5627G7512G16949和药效G3254G8181G3423的叠和程G5242，可G1209G4557每G1022化G2524G10301G17839G15904G8975G5627G20056G8991。化G2524G10301G8975G5627G7512G16949与G7380佳药效G3254G8181G3423的匹配G5627G2462G8975G5627G20056G8991值等G6980G6466见表2。TABLE2THEMATCHINGOFCOMPOUNDSWITHPHARMACOPHORENOFITMAPPINGESTIMATEDACTIVITYACTUALACTIVITY1833204660300790928387466030071238337556030079053482575560300940745874752446603003104766361951317440076477255157540864325551631809627725519026106402575167160116566855146861263972551682413650195851542614654562532483415644672531618116620683410110211768171581912610185985532361801201964119242651302066862191423594216545934149120226423624264832364644555658332467814810152817256691311015341326723148601010112774748601015577728705148601015929661131101542413067648631015301331766103112137523268341431525533366045734250346554315486035652573155199366836431315251137714644315121538650604575454396401542267140406293820248624041714242056151220426323820248125043644245730612304460056242017032045625245115941204665138242058534847656758304718486223820241001704965620383046825059554203019035051656204530462005264674530582253651203445305280546512434305210055664244530391056643203445306234576552434304828586492464343055665964520343060886082750246430091096178069245630271627975020443018086369063155412115647614830187413665663374284022666494481954896764287467642868626844339352696294735678726706415035286633716975036195189172720594751311107372926431913869374710154319131344757695943513353767173525111557771863445111197866544513899796594551446580664424553994817603612211542128272837648158874为了G17839一G8505考察G6164G5326G12447的AT1受体拮抗剂的药效G3254G8181G3423的适用G5627，G7424G7003G17885G6333了化G2524G10301G19610G1209G38189G1022G7003G10498G6265G17959的G5062G990市的AT1受体拮抗剂或G1866G1207谢G8975G5627产G10301（化G2524G103018391）与G7380佳药效G3254G8181G3423G17839G15904了叠和，G5194G4557G1866G8975G5627G17839G15904了G20056G8991。化G2524G10301G13479G7512，G8975G5627G7512G16949的能量值，与G8181G3423的匹配G5627G1209G2462G8975G5627G20056G8991值等G1867体G6980G6466见表3TABLE3THEMATCHINGOFOTHERCOMPOUNDSWITHPHARMACOPHORENOCOMPOUNDFITESTIMATEDACTUALECONFORMACTIVITYACTIVITY/KCALMOL18365374935140188465854454918985654748191005186605353122504876702345501394388648556328728963427735014992906827252772869162595284070THEDATAOFIC50FROMREF6COMPD83,89,11COMPD84,8COMPD85,15COMPD86,16COMPD87,13COMPD88,14COMPD90,17COMPD91,SEPARATELYG1866中化G2524G1030183为G8943G8813G3386，是第一G1022G990市的AT1受体拮抗剂，G2045用药效G3254G8181G3423G20056G8991的G8975G5627值与G4466G20576值G17751接近（FIT6537,G20056G8991值49NMOLL1，G4466G8991值35NMOLL1）。G1866与药效G3254G8181G3423叠G2524的G13479果（G32823）可G1209看G1998，G8943G8813G3386的G13479G7512与药效G3254G8181G3423的叠和不是很好，G1866中的氢G19202受体（HBA）没有叠G2524，表明G1866G17836有改造的余地。G4466际G990G8943G8813G3386的G8975G5627不是G7380佳，后G7481的化G2524G10301G8975G5627G3355超过G8943G8813G3386。FIGURE3MAPPINGOFTHECOMPOUND83ONTOTHEOPTIMALPHARMACOPHOREMODEL现在G990市的G16825G12879药G10301G18618种,G17839入临床研究阶段的有40G3822种化G2524G10301,G3835G3822是G1209G8943G8813G3386为原G3423,G4557G1866各G1022部G1313G17839G15904修饰和改造而获得的。美国杜邦G1856G2508发现根G6466ANG的C末端肽分子TYRILEHISPROPHEG7512G16949,G2524成的拮抗剂应G1867有G2528G1209下G13479G7512相吻G2524的部分C末端羧G3534侧链与ILEG13479G7512相似的脂肪烃侧链能与N末端成氢G19202G13479G2524的中心。G7512效关系表明在苄G3534G4557G1313引入1G1022额G3818的G14531环,G7512成联G14531G13479G7512,生G10301G8975G5627G6564高。G312引入的G14531环G18063G1313有一G18252G5627官能G3254,G18252G5627G17246强G1158和力G17246G3835,G1375G3926CN、COOME、CF3、CONH2等G3355能G17810G2052和羧G18252相G2528的G1158和力,四G8706G2789不G1177G3926G8504,而且4G1022G8706原子能G4493G13447G17139G11017G14667分G5079与受体G990G8503G11017G14667中心相互作用,效果G7368好。G313末端G14531环G990的G18252G5627G2474G1207G3534G1313置G2325分重要,2、6G260G1313G2464G2474G1207G1363联G14531不在G2528一G5191面G5194且G1363G7071转G19568G11873G3698G2164,会G4560G14280G1158G2524力下G194891G1022G6980量级。G314G2686G2789环的2G1313G2474G1207G3534为G19283G524234G1022G11911原子的G1158脂G5627侧链,G3926G8503G9931烃而G6915链G9931烃、环G9931烃和芳香G2474G1207G3534G3355G19489低G1158G2524力。G315G2686G2789环4G1313G7380好是1G1022G1158脂G5627的G3835功能G3254或G3534G3254。G316G2686G2789环5G1313G2474G1207G3534为能形成氢G19202的G4579G3534G3254,G3926G18267、醛、G18252等18。G7003G10498G6265G1795919G1209G6164得分子力G4410G13479G7512参G6980为变量,G4557化G2524G10301抑制AG16837G4560的G1832G14028主G2172G14045环G6922G13565的AT1受体拮抗G8975G5627PA2值G17839G15904G3250G5414分G7524得G2052的QSAR方程表明AT1受体拮抗剂的G8975G5627与分子偶G7509G11709、分子的G1158脂G5627、分子二面G16294G1209G2462N1原子G2052G18252G5627G3534G3254的距离G2588G8503相关而与分子的非G8503G2029能、范G5515G2338能等G3252素G2588G17139相关。G7424G7003G6164G6564G1998的药效G3254G8181G3423G3534G7424G12538G2524G2081G1166的研究G13479论，G1186而说明G8943G8813G3386的G3534G7424G13479G7512在改G17839之后，可G1209获得G7368好的G8975G5627，G2528G7114也G20576G16789了G2081G1166G4557G8943G8813G3386G7512G3423G17839G15904改造的方G2533是非常G8503确的。G7424G8181G3423G7186G12046G1998了一定的G8975G5627G20056G8991能力，为G17839一G8505的G20056G8991化G2524G10301G8975G5627和G16786G16757G7044G3423G13479G7512的AT1受体拮抗剂G6564供了理论G3534G11796。A110A111A112A113A112A113A114A115A116A117A118A119A120A121A122A123A124A125A126A127A128A129A130A131A132A133A134A135A123A124A136A137A138A139A140A141A142A143A144JA145A146A147A148A149A150A151A148A152A153A1201998,256A154231A155A156A157A158A159A160A161A162A163A164A165A159A160A166A159A167A168A169A164A170A171A172A173A174A159A173A166A175A176A177A164A172A175A159A178A179A168A180A181A172A159A173A175A169A164A182A183A183A184A164A182A156A185A186A187A188A189A182A190A191A191A192A182A184A193A182A155A190A157A194A173A159A175A159A181A164A195A196A172A174A180A158A164A162A174A197A178A197A198A168A164A172A175A159A178A179A181A167A180A159A160A199A174A200A180A159A201A172A189A199A172A178A178A167A178A159A173A178A196A199A159A178A197A202A159A175A197A196A160A159A160A166A173A172A161A197A196A160A159A178A166A197A201A175A173A197A171A167A175A197A196A160A196A203A159A180A159A204A196A173A159A160A161A197A196A175A172A160A201A197A160A205FORMINGENZYMEINTHEHEARTJCLININVEST,1993,91,126912814XUXJ,HOUTJ,QIAOXB,ETALCOMPUTERAIDEDDRUGDESIGNA206A207A208A209A210A211A212A213A214A215A206MBEIJINGA216CHEMICALINDUSTRYPRESS,2004A2162955DALJITSDHANOA,SCOTTWBAGLEY,ETALDIPROPY1PHENOXYPHENYLACETICACIDSANEWGENERATIONOFNONPEPTIDEANGIOTENSINI1RECEPTORANTAGONISTSJMEDCHEM1993,36,373837426UWEJRIES,GERHARDMIHM,ETAL6SUBSTITUTEDBENZIMIDAZOLESASNEWNONPEPTIDEANGIOTENSINI1RECEPTORANTAGONISTSSYNTHESIS,BIOLOGICALACTIVITY,ANDSTRUCTUREACTIVITYRELATIONSHIPSJMEDCHEM1993,36,404040517CARMENALMANSA,LUISAGOMEZ,ETALDIPHENYLPROPIONICACIDSASNEWAT1SELECTIVEANGIOTENSINIIANTAGONISTSJMEDCHEM1996,39,219722068ANDREACAPPELLI,GALLAPERICOTMOHR,EAALFURTHERSTUDIESONIMIDAZO4,5BPYRIDINEAT1ANGIOTENSINIIRECEPTORANTAGONISTSEFFECTSOFTHETRANSFORMATIONOFTHE4PHENYLQUINOLINEBACKBONEINTO4PHENYLISOQUINOLINONEOR1PHENYLINDENESCAFFOLDSJMEDCHEM2006,49,645164649ILASIRCAR,RTHOMASWINTERS,ETALNONPEPTIDEANGIOTENSINI1RECEPTORANTAGONISTS1SYNTHESISANDINVITROSTRUCTUREACTIVITYRELATIONSHIPSOF41WPYRROLLYLACETYLAMINOPHENYLMETHYLIMIDAZOLEDERIVATIVESASANGIOTENSINI1RECEPTORANTAGONISTSJMEDCHEM1993,36,1735174510DALJITSDHANOA,SCOTTWBAGLEY,ETALNONPEPTIDEANGIOTENSINI1RECEPTORANTA