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SYBYL-SYBYL- SYBYL-XistheBESTchoiceforMolecular源資信息科技()計(jì)算機(jī)輔助藥物TopomerTopomer虛擬從頭分子藥效團(tuán)模基于基于藥物同源同源組合Tripos公司計(jì)算機(jī)輔助藥物設(shè)計(jì)藥物設(shè)計(jì)與分子模擬專SYBYL-XSYBYL-分子表面及其性質(zhì)可視化的高計(jì)算分子的表面和溶劑可及表將疏水性、靜電Vitamin表面積體積球棍模

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---靜電 的分子表分子表面及其性質(zhì)可視化的高級(jí)功將 面(靜電勢(shì) 基于配體的藥物構(gòu)效關(guān)系和ADME–Topomer–Topomer–QSARwith–Advanced–Surflex-藥效QSARQSARwith建立3D-QSAR模型CoMFA:ComparativeMolecular 藥物與受體之間沒有形成共價(jià)鍵，只有非鍵相互作藥物活性的改變與場(chǎng)或（和）靜電場(chǎng)的改變相 分子場(chǎng)分子場(chǎng)結(jié)分結(jié)

f(C統(tǒng)計(jì)IC50,IC50,生物活性于能強(qiáng)模形、觀已漸Q方法場(chǎng)Cramer,R.D.,etal.(1988).J.Am.Chem.Soc.110(18):5959-QSARQSARwith建立3D-QSAR模型CoMSIA:ComparativeMolecularSimilarity 藥物與受體之間沒有形成共價(jià)鍵，只有非鍵相互作藥物活性的改變與場(chǎng)、靜電場(chǎng)、疏水場(chǎng)、氫鍵供（受）體場(chǎng)分子場(chǎng)(C’)它們的組分子場(chǎng)(C’)結(jié)分結(jié)

f(C統(tǒng)計(jì)方IC50,IC50,生物活性QSARQSARwith建立3D-QSAR模型(J.Med.Chem.,1999,42(3),pp–改造后的抑制劑(以藍(lán)色顯示的化合物)，親和力增加了100場(chǎng)

疏水藍(lán)色QSARwith建立3D-QSAR模型3D構(gòu)象生Topomer快捷方便地建立3D-QSAR–不需要疊合的3D-–快速、高–完整的分子被分成兩個(gè)或多個(gè)碎片，并生成碎片的三維構(gòu)–碎片上被斷的旋鍵被合三的個(gè)定矢量–碎片構(gòu)象按照一定經(jīng)驗(yàn)規(guī)則進(jìn)行調(diào)整，得到CoMFAII——TopomerFive-MinutesAutoNo-AlignmentSearched

快速自動(dòng)完成可用于虛擬Topomer快捷方便地建立3D-QSAR3D構(gòu)象3D構(gòu)象生3D-QSAR:topomerCoMFA(J.Med.Chem.44,2691-2694TopomerTopomerTopomerCoMFA在藥物發(fā)現(xiàn)項(xiàng)目中的細(xì)胞色素CYP2C9在PubChem似的化根據(jù)模型設(shè)計(jì)新化合成和生物臨床前研究……FDAWendt,B.;Mülbaier,M.;Wawro,S.;Schultes,C.;Alonso,J.;Janssen,B.;Lewis,J.Med.Chem.2011,inTopomerCoMFA?+TopomerTopomerCombineCombineTopomerCoMFAandTopomer …………… ……… O…O…N… ……… ……………SomeprospectiveLeadHopsfromTopomerQuery Alpha-

0.11301.1(Crameretal.,JMC2004,Howdiscovery-relevantareRGVSsearch(searcheswerewithinZINC,18pIC50overhighest

#ofalternativeR-groupCramer,R.D.;Cruz,P.;Stahl,G.;Curtiss,W.C.;Campbell,B.;Masek,B.B.;Soltanshahi,F.J.Chem.Inf.Model.2008,48,2180-SYBYLSYBYL藥效團(tuán)數(shù)據(jù)庫(kù)搜分子疊Zhu,H.,etal.(2008).DrugDiscoveries&TherapeuticsJ.MED.CHEM.2009,52,基于受體的藥物分子–Surflex-從頭–EA-分子對(duì)接和虛擬篩 的準(zhǔn)Pham,T.A.Des,2008.數(shù)據(jù)Pons,J.,N.J.P.Girault,Transactivatingtranscriwithbeta-catenin.

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ntstructureoftranscriptionatesinstructure-eadvantages分子分子對(duì)接和虛擬?–Surflex-Dock使用原型分子（Protomol）表示蛋白的結(jié)合口++ =分子對(duì)接和虛擬 對(duì)接物晶體結(jié)構(gòu)1B9Vddn

分子對(duì)接和虛擬篩 /article/pressRelease/idUS171062+17-Feb-5百萬(wàn)個(gè)化合21400個(gè)-------------------- 真陽(yáng)性率（TruePositiveYieldTP）高TPattop2.5%ofhit TPattop5%ofhitSurflex-

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Protein蛋白柔性對(duì)ProblemswithprotonationPDBfilescomewithouthydrogensandautomaticadditionofHcanbeDockinginto RMSD=8.57Protein+ligandminimizedindockingforce1apt1apt minimizedcrystalTopScoringPose(“cooked RMSD=0.16surflex-dock-v2207.exepoptligand_reference.mol2protein.mol2(producesopt.mol2andpopt.mol2)surflex-dock-v211.exeprotoopt.mol2popt.mol2lig分子對(duì)接和虛擬篩點(diǎn)點(diǎn)Surflex-獨(dú)特的應(yīng)用：以DNA為靶嵌插結(jié)合 Wang,L.andT.E.Mansley(2008)"Surflex-DockingIntoTheMinorGrooveofDNA."限制性對(duì)一致性評(píng)分函–從統(tǒng)計(jì)學(xué)上講，經(jīng)驗(yàn)打分函數(shù)其質(zhì)量取決于訓(xùn)練集。雖然研究者總AACaseStudy(PNASJuly1,2008vol.105no.269099-9104研究 活性與實(shí)驗(yàn)結(jié)果一(E)-

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α- Ki>20從頭藥物設(shè)計(jì) 1) 2)Liu,Q.,etal.(2007).JMedChem50(22):5392-DeNovoDesignof olarNonbasic5-HT1BReceptor新型5-HT1B受體拮抗劑的發(fā)現(xiàn)（左：先導(dǎo)化合物；右：新化合物J.Med.Chem.2010,53(4),ppAnAnExampleofhowanInventionNNONNO325NK1NNONNO32225NK1ONNInitialONNInitial4.0-3222330-25-52-?Tripos,L.P. SlideGenerationGenerationONNInitial32222225-52-4?Tripos,L.P. SlideInitialNN GenerationGenerationO32222222330-25-52-44?Tripos,L.P. SlideInitialNN GenerationGenerationO322222222252-444?Tripos,L.P. SlideInitialNN GenerationGenerationO32222222222225-52-4443GenerationGeneration?Tripos,L.P. SlideInitialNN GenerationGenerationO32222222222225-52-4443GenerationGenerationNNNN?Tripos,L.P. SlideInventingDrug-likeorSynthesizableBuildwithaDrug-likeFragment Fragmentsandprobabilitiesderived ysisofNNNNNNOO

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SynthesisOperator(e.g.gensynfromSyntheticAccessibilityScore(LiterallyANYscoring?Tripos,L.P.sStructuralBiologyand結(jié)構(gòu)生物學(xué)與生物信–AdvancedAdvancedAdvancedProtein結(jié)構(gòu)生AdvancedProteinModelingAPM=FUGUE+ORCHESTRAR折疊識(shí)同源識(shí)序列比比較建SequenceModelStructurallySequenceModelStructurallyConservedModelStructurallyVariableAddValidate… ModelNayeemetal:Protein2006,15,808-Hardest:15-20%SequenceIdentityCSYBYLDSAdvancedProtein同源性(homology)，相似性(similarity)，一致性cn員是源，是些列化較以度:26% APMAPM與Surflex-Dock聯(lián)用案(J.M.M.,2009,15,1145-Homologymodelingofhumanα1β2γ2andhouseflyβ3receptorchannelsandSurflex-dockingofLibraryLibrary組合化組合化學(xué)庫(kù)生分子虛擬組合庫(kù)設(shè)計(jì)的步2、選擇合適的組合合成策略，即定義結(jié)構(gòu)的取