SYBYL软件与计算机辅助药物设计

1、1会计学SYBYL软件与计算机辅助药物设计软件与计算机辅助药物设计第2页/共59页第3页/共59页第4页/共59页湘潭师范学院湘潭师范学院桂林工学院桂林工学院重庆工学院重庆工学院大连理工大学大连理工大学武汉化工学院武汉化工学院香港中文大学香港中文大学香港浸会大学香港浸会大学第5页/共59页第6页/共59页第7页/共59页药物研发的进程药物研发的进程*courtesy Merck-FrosstDrug Design ProcessBIOTECHTRIPOSDiscovery Phase第8页/共59页 第一个SBDD方法设计的新药碳酸酐酶抑制剂Dorzolamide (治疗青光眼疾病)于1994

2、年上市Wellcome公司用CADD方法设计的5HT1D受体激动剂 311C90 (治疗偏头痛) ，进入三期临床研究 美国Eli Lilly公司开发的第一个高效、高选择性人体非胰腺分泌型磷脂酶抑制剂LY311727,进入临床研究4个已上市的HIV-1蛋白酶抑制剂类药物的研制过程中，计算机辅助药物设计起了重要作用2个凝血酶抑制剂已进入临床研究Glaxo开发的唾液酸酶抑制剂4-胍基Nen5Ac2en (抗感冒药物)进入临床研究 治疗糖尿病药物(醛糖还原酶抑制剂)上市计算机辅助药物设计成功的例子计算机辅助药物设计成功的例子第9页/共59页Software Introduction第10页/共59页S

3、oftware Introduction第11页/共59页 Tripos Total Solutions第12页/共59页Modelling & VisualisationSYBYL/Base（基础平台）基础平台）AMPAC（半经验量化）半经验量化）MOPAC （半经验量化）半经验量化）MM3_2000 （分子力学）分子力学）MOLCAD（图形显示）图形显示）Advanced Computation（构像分析）构像分析）第13页/共59页GraphicswindowTextportSoftware Introduction第14页/共59页Modelling & Visuali

4、sation第15页/共59页10 conformations95 conformationsTorsion angleModelling & Visualisation第16页/共59页QSAR第17页/共59页QSAR & ADME第18页/共59页QSAR & ADME第19页/共59页Structures + ActivitypKi=5.3pKi=3.7pKi=2.9DescriptorslogP = 1.9m m = 2.8Estate = 7.2logP = 2.1m m = 3.5Estate = 5.5logP = 1.7m m = 2.3Estate

5、= 6.7 Predicitive Model (QSAR Equation)pKi=A + B(logP) + C(m m) + D(Estate) + .PLSMLR.QSAR & ADME第20页/共59页pKi =B(D1)+C(D2)+ .APLSQSAR & ADME第21页/共59页Less steric bulkMore negative chargeQSAR & ADME第22页/共59页A = 吸收吸收, D=分布分布ADME第23页/共59页 Hydrophilic regions (8) Interaction volumes of water

6、probe -1.0, -4.0kcal/mol 8 Integy moments -0.2, -0.5, ., -5.0, -6.0 kcal/molIntergy moments-4.0 kcal/molInteraction Volume-1.0 kcal/molInteraction VolumeADME第24页/共59页Pharmacophore perceptionDISCOtechGASP第25页/共59页SulphurRingNitrogen rich section what do they have in common in 3D?H-bond DonorH-bond Ac

7、ceptorHydrophobePharmacophore perception第26页/共59页H-bond DonorH-bond AcceptorHydrophobeH-bond DonorH-bond AcceptorHydrophobex1,y1,z1x2,y2,z2x3,y3,z3x4,y4,z4x5,y5,z5Spatial query - pharmacophore points specified by x,y,zD1D2D3D4Distance query - pharmacophorespecified by interfeature distances D1, D2,

8、.Pharmacophore perceptionHit molecule from LeadScreen第27页/共59页MolecularStructuresLow EConformationsPharmacophoreModelConformergenerationCliquedetectionPharmacophore perception第28页/共59页MolecularStructuresPharmacophoreHypothesesAlignmentChromosomesMutationCrossoverPharmacophore perception第29页/共59页Chem

9、ical InformaticsUNITY（数据库管理与搜索）数据库管理与搜索）CONCORD /SteroPlex （2D-3D）SARNavigator（高通量筛选数据分高通量筛选数据分析）析）第30页/共59页Chemical Informatics第31页/共59页NSOOSearch Takes 8 seconds and returns 84 compounds Chemical Informatics第32页/共59页Search Takes 7 seconds and returns 8 compounds Chemical Informatics第33页/共59页Biomol

10、ecular SoftwareBiopolymer（生物大分子）生物大分子）Composer（同源模建）同源模建）MatchMaker（穿线法）穿线法）GeneFold（复合穿线法）复合穿线法）FUGUE（远程同源模建）远程同源模建）ProTable（蛋白质结构分析蛋白质结构分析）SiteID（结合位点分析）结合位点分析）LeapFrog（从头设计）从头设计）Rachel第34页/共59页生物大分子显示，修改，优化生物大分子显示，修改，优化Biomolecular SoftwareSequence: FVNQHLCGSHLVEALYLVCGERGFFYTPKA第35页/共59页Biomolec

11、ular Software第36页/共59页Biomolecular SoftwareKnown proteinstructureFVNQHLCGSHLVEALYLVCGERGFFYTPKAHYGRTSKGTPSVENIYLKFFGPMRSYLPTGProteinsequenceHYGRTSKGTPSVENIYLKFFGPMRSYLPTGPredict structureHYGRTSKGTPSVENIYLKFFGPMRSYLPTGAlign to get scoresequence & structureBiomolecular Software第37页/共59页比对和评分矩阵，为低同

12、源性的目标蛋白找到高质量的构建模板。第38页/共59页Compute structurequality data in MSSAnd visualise it onthe actual structureBiomolecular Software第39页/共59页Virtual ScreeningFlexXFlexX-PharmCscoreCombiFlexXFlexS第40页/共59页 G=-RTlnKi基于结构的虚拟筛选基于结构的虚拟筛选With all of its weaknesses, structure-based screening through docking is matu

13、re enough to be considered as a first-line technique in pharmaceutical discovery research。Current opinion in chemical biology 2002 6: 439-446第41页/共59页成功案例成功案例Hou T. J. Xu. X. J. Current Pharmaceutical design (In press)Target Activity 1. Human carbonic anhydrase 0.6 nm (IC50) 2. AmpC b-lactamase 26 (

14、Ki) 3. b-adrenergic receptor kinase 1 (bARK1) 126 (IC50) 4. Thymidalate synthase 1.4 (Ki) 5. Aldose reductase (ALR2) 0.10 (IC50)6. Adenovirus proteinase 3.09 (Ki) 7. Bcl-2 10 (IC50) 8. Aldose reductase 4.3 (IC50) 9. Matriptase 0.92 (IC50) 10. Retinoic acid receptor 2 (ED50) 11. Dihydrodipicolinate r

15、eductase 7.20 (Ki) 第42页/共59页Virtual Screening第43页/共59页LigandbasefragmentBindingSiteonProteinOnemappingofligandtoreceptorVirtual Screening第44页/共59页第45页/共59页Virtual Screening第46页/共59页PPAR-基因转录因子，以配体激活方式调控脂肪细胞分化。 PPAR激动剂是很有前途的胰岛素增敏剂,2种新药2000年FDA批准在美国上市，其中罗格列酮(GSK)销额$10亿(20002001年）。Virtual Screening第47页

16、/共59页DatabaseScreen with DOCKTop 1%10%Screen with FlexXLead Compounds 2 Million CompsVirtual Screening第48页/共59页PPAR (Peroxisomeproliferator-activatedreceptor)Large-Scale Virtual Screening 2 Million Comps.15 years of WSACD-3D1101001k10k100k1M Number of Compound600,00010,00050020040Drug Like Expert Se

17、lectDeep VSInitial VSPPAR Agonist Discovery Process7ExperimentVirtual ScreeningMDDR第49页/共59页1.8810-6 DDDC_P_16 7.3510-7 DDDC_P_15 3.1410-8 DDDC_P_14 1.1610-6 DDDC_P_13 8.2610-7 DDDC_P_12 1.2110-6 DDDC_P_11 5.8510-8 DDDC_P_10 1.1010-6 DDDC_P_09 1.8710-7 DDDC_P_08 8.1310-8 DDDC_P_07 1.2910-8 DDDC_P_06

18、 1.1010-7 DDDC_P_05 7.5810-7 DDDC_P_04 2.9410-7 DDDC_P_03 1.1110-7 DDDC_P_02 2.0010-7 DDDC_P_01阳性对照药阳性对照药1.5210-8 (reference 910-8 ) Troglitazone 阳性对照药阳性对照药1.5110-5(reference 1.16 10-5 ) 15-d-PGJ2 阳性对照药阳性对照药3.4010-9 (no reference) Gi262570 Ki常数常数 化合物序号化合物序号 Virtual Screening第50页/共59页PPARDDDC-P-06com

19、plexesVirtual ScreeningCrystal第51页/共59页Diversity and CombiChemLegionCombiLibMakerDiverseSolutionsSelector第52页/共59页Diversity and CombiChemR1R2OOR3NNR4+15 diketones 31 hydrazines 465 productsNNR4R1R3R2第53页/共59页Filter the databaseExcluded/includedcompoundsFiltering criteriaDiversity and CombiChem第54页/共

20、59页NNNH2HMeNNNNH2MeMolecularFragments.01101111111MolecularFingerprint0512018359102MolecularHologramIntercompound distance from Tanimoto or Cosine coefficients, Hamming distanceDiversity and CombiChem第55页/共59页Vector representation of fields compared by: Euclidian distance Tanimoto coefficient Cosine coefficientDiversity and CombiChem第56页/共59页CompoundSelect compound at randomPick most different compound from 1stPick most different compound from selectedDiversity and CombiChem第57页/共59页Com