SYBYL软件与计算机辅助药物设计课件

,Click to edit the title text format,Click to edit the outline text format,Second Outline Level,Third Outline Level,Fourth Outline Level,Fifth Outline Level,Sixth Outline Level,Seventh Outline Level,Eighth Outline Level,Ninth Outline Level,凯鹏视算,Click to edit the title text format,Click to edit the outline text format,Second Outline Level,Third Outline Level,Fourth Outline Level,Fifth Outline Level,Sixth Outline Level,Seventh Outline Level,Eighth Outline Level,Ninth Outline Level,凯鹏视算,Click to edit the title text format,Click to edit the outline text format,Second Outline Level,Third Outline Level,Fourth Outline Level,Fifth Outline Level,Sixth Outline Level,Seventh Outline Level,Eighth Outline Level,Ninth Outline Level,凯鹏视算,SYBYL,软件与计算机辅助药物设计,Zuowei Yan,ChemBay Technology Ltd,Feb,23, 2004,SYBYL软件与计算机辅助药物设计Zuowei Yan,凯鹏视算技术有限公司,面向国内医药、化学、生命科学、农药领域,的科研院校及工业部门，提供新化合物研发,的软硬件解决方案技术支持和咨询服务。,凯鹏视算技术有限公司面,美国,Tripos,公司是业界非常著名的高科技公司。,Tripos,的主营业务包括三个方面：新化合物研发软件产品软件咨询服务新化合物的研发与销售世界上最大的15家制药公司都购买了,Tripos,的软件产品作为重要的研究手段。,美国Tripos公司是业界非常著名的高科技公司。 T,Tripos Research and Service,软件产品,SYBYL/UNITY,SARNavigator,化合物实体,LeadQuest,LeadScreen,LeadHopping.,软件咨询与售后服务,Chembay Service in P.R.China,Tripos Research and Service软,User Lists-,高等院校,北京大学物理化学研究所、化学与分子工程学院、蛋白质工程和植物基因工程国家重点实验室、医学部药学院,清华大学化学系、生命科学与工程研究院,北京工业大学环境化学系、生命科学学院,北京中医药大学中药学院,山东大学药学院,中国科学院研究生院,南开大学元素有机化学研究所,天津师范大学晶体所,沈阳药科大学药物研究所,吉林大学理论化学研究所,中国海洋大学海洋食品及药物研究所,User Lists-高等院校北京大学物理化学研究所、化学与,User Lists,-,高等院校,南京大学化学系、环境科学系,浙江大学化学系、药学院,复旦大学化学系、药学院,中山大学生命科学学院,第二军医大学药学院,中国药科大学药学院,厦门大学化学系,兰州大学计算机化学研究所,华中师范大学农药所,云南大学现代生物中心,湘潭师范学院,桂林工学院,重庆工学院,大连理工大学,武汉化工学院,香港中文大学,香港浸会大学,User Lists-高等院校南京大学化学系、环境科学系湘潭,中国科学院上海药物研究所,中国科学院上海有机研究所计算机化学开放实验室,中国科学院上海有机研究所国家生物有机及天然产物重点实验室,中国科学院贵州省天然产物化学重点实验室,中国科学院上海生物工程研究中心,中国科学院化工冶金研究所计算机化学开放实验室,中国科学院昆明动物研究所,中国科学院昆明植物研究所,中国科学院武汉物理研究所,中国科学院广州化学研究所,中国科学院长春应用化学研究所,中国科学院上海分院,User Lists-,科研院所,中国科学院上海药物研究所 User Lists-科研院所,中国医学科学院北京药物所有机合成室,中国医学科学院北京药物所国家药物及代谢产物分析研究中心,中国医学科学院天津血液学研究所,北京药物化学研究所北京微生物流行病研究所,四川抗菌素研究所,上海医药工业研究院,上海转基因研究所,江苏农药研究所,东北制药集团,山东大学药学院,南京大学化学院,天津药物研究院,军事医学科学院,User Lists,-,科研院所+工业部门,中国医学科学院北京药物所有机合成室 User Lists-科,药物研发的进程,*,courtesy Merck-Frosst,Drug Design Process,BIOTECH,TRIPOS,Discovery Phase,药物研发的进程*courtesy Merck-FrosstD,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,年上市,Wellcome,公司用,CADD,方法设计的,5,HT1D,受体激动剂,311,C90,(,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,第一个SBDD方法设计的新药碳酸酐酶抑制剂Dorzolami,Tripos Software,SYBYL,& its modules,SYBYL,Concord sketch,MOLCAD,SiteId,Advanced Computation,GASP,DISCOtech,HQSAR,QSAR,AMPAC,Advanced CoMFA,Distill,clogP/CMR,Biopolymer,Composer,GeneFold,ProTable,MatchMaker,Leapfrog,HiVol,CombiLibMaker/Legion,CLM 3D option,PowerCLM,DYANA,Dynamics,Selector,Triad,Mardigras,FlexS,CScore,Confort,Confort 3D option,Concord standalone,Power Concord,Stereoplex,DiverseSolutions,Receptor,MM2/3,VolSurf,FlexX,CombiFlexX,FUGUE,FlexX-Pharm,Unity,Unity Base,Unity 3D,Unity Extra Search Engine,Software Introduction,Tripos SoftwareSYBYL & its mod,SYBYL,and UNITY,Solutions,建模和显示,基于配体的设计(,定量构效关系和药效团分析,),化学信息学,组合化学库设计与分子多样性,结构生物学和生物信息学,从头药物设计,虚拟筛选,核磁数据辅助解析,Software Introduction,SYBYL and UNITY Solutions建模和,Tripos Total Solutions,Tripos To,Molecular Modelling & Visualisation,分子建模与可视化,Modelling & Visualisation,SYBYL/Base（,基础平台）,AMPAC（,半经验量化）,MOPAC （,半经验量化）,MM3_2000 （,分子力学）,MOLCAD（,图形显示）,Advanced Computation（,构像分析）,Molecular Modelling & Visualis,SYBYL,Graphics,window,Text,port,Software Introduction,SYBYLGraphicsTextSoftware Intr,MOLCAD,Modelling & Visualisation,MOLCADModelling & Visualisatio,Advanced Computation,Advanced Computation,内置了多种构像分析的工具。包括系统构像搜索法，格点构象搜索法，随机搜索法，基于遗传算法的构像分析。,帮助用户确定分子的优势低能量构象，为,QSAR，,药效团分析等等模块提供素材。,Systematic search example,10,conformations,95,conformations,Torsion angle,Modelling & Visualisation,Advanced ComputationAdvanced C,QSAR,& ADME,定量构效关系与药动学性质预测,QSAR with CoMFA（,比较场分析）,Advanced CoMFA,HQSAR（,全息法定量构效关系）,ClogP/CMR（,疏水参数与分子折射率）,Distill（,公共子结构分析）,MolConnZ（,拓扑指数）,QSAR,QSAR & ADME定量构效关系与药动学性质预测QSAR,QSAR & ADME,Modules,QSAR with CoMFA,Advanced CoMFA,HQSAR,clogP/CMR,Distill,VolSurf,研究的内容,计算与化合物活性性质相关的结构特征,构建预测化合物活性的模型,生物活性,ADME,性质,根据模型预测活性和,ADME,性质,在药物发现中所起的作用,为筛选和合成新化合物提供信息,为药物设计提供新思路,QSAR & ADME,QSAR & ADMEModulesQSAR & ADME,QSAR,的工作原理,Quantitive Structure Activity Relationships,建立生理活性与可计算的分子性质之间的关系,以数值的方式描述活性,以数值的方式来描述分子的性质,合理的统计方法使活性与描述符相关,重要的影响因素,models must be predicitive - or theyre useless（,可预测性）,models should be interpretable - where possible（,可解释性）,QSAR & ADME,QSAR 的工作原理Quantitive Structure,Structures + Activity,pK,i,=5.3,pK,i,=3.7,pK,i,=2.9,QSAR - Traditional (2D),传统定量构效关系计算的分子性质,logP, dipole moment, connectivity indices ,问题是必须选择那些重要的描述符,Descriptors,logP = 1.9,m,= 2.8,Estate = 7.2,logP = 2.1,m,= 3.5,Estate = 5.5,logP = 1.7,m,= 2.3,Estate = 6.7,Predicitive Model (QSAR Equation),pK,i,=A + B(logP) +,C(,m,) + D(Estate) + .,PLS,MLR,.,.,QSAR & ADME,Structures + ActivitypKi=5.3pK,QSAR - 3D QSAR - CoMFA,Co,mparative,M,olecular,F,ield,A,nalysis(,比较分子场分析),描述符是分子周围的化学环境，包括静电，立体，氢键，疏水场,pKi =,B(D,1,),+,C(D,2,),+,+ .,A,PLS,QSAR & ADME,QSAR - 3D QSAR - CoMFAComparat,CoMFA -,Interpretation,与活性高度相关的网格被用某些特定的颜色标记出来，指示用户修饰分子的思路。,Less steric bulk,More negative charge,QSAR & ADME,CoMFA - Interpretation与活性高度相关的,ADME - VolSurf,与,QSAR,一致的方法和思路,计算,ADME,相关的描述符,PLS or PCA,方法分析,描述符的种类,72 descriptors - 5 classes,Size & Shape（,分子的形状）,Hydrophilic regions（,亲水区域）,Hydrophobic regions（,疏水区域）,INTEraction enerGY (,亲和能量),Mixed descriptors（,混合的描述符）,预先计算好的模型,CACO2 permeability (A,D), skin permeability (A), Blood-Brain barrier (D), LogP,A =,吸收,D=,分布,ADME,ADME - VolSurf与QSAR一致的方法和思路,Descriptors - visualisation,Hydrophilic regions (8),Interaction volumes of water probe -1.0, -4.0kcal/mol,8 Integy moments -0.2, -0.5, ., -5.0, -6.0 kcal/mol,Intergy moments,-4.0,kcal/mol,Interaction Volume,-1.0,kcal/mol,Interaction Volume,ADME,Descriptors - visualisationHyd,Pharmacophore Perception,药效团分析,Pharmacophore perception,DISCOtech,GASP,Pharmacophore Perception药效团分析,What is a Pharmacophore?,例子 -,Tagamet and Zantac,在体内具有相同的生物学效应,结合到相同的受体,what do they have in common in 2D?,Sulphur,Ring,Nitrogen rich section,what do they have in common in 3D?,H-bond Donor,H-bond Acceptor,Hydrophobe,Pharmacophore perception,What is a Pharmacophore?例子 - T,药效团分析模块的应用,3,D database queries,and molecular alignments,H-bond Donor,H-bond Acceptor,Hydrophobe,H-bond Donor,H-bond Acceptor,Hydrophobe,x1,y1,z1,x2,y2,z2,x3,y3,z3,x4,y4,z4,x5,y5,z5,Spatial query - pharmacophore points specified by x,y,z,D1,D2,D3,D4,Distance query - pharmacophore,specified by interfeature distances D1, D2, .,Pharmacophore perception,Hit molecule from LeadScreen,药效团分析模块的应用3D database queriesH,DISCOtech,的工作原理,Molecular,Structures,Low E,Conformations,Pharmacophore,Model,Conformer,generation,Clique,detection,Pharmacophore perception,DISCOtech 的工作原理 MolecularLow E,How does GASP work?,Molecular,Structures,Pharmacophore,Hypotheses,Alignment,Chromosomes,Mutation,Crossover,Pharmacophore perception,How does GASP work?MolecularPh,Chemical Informatics,化学信息学,Chemical Informatics,UNITY（,数据库管理与搜索）,CONCORD /SteroPlex （2D-3D）,SARNavigator（,高通量筛选数据分析）,Chemical Informatics化学信息学 C,Unity,通过多种手段对数据库进行搜索,二维子结构搜索,分子相似度搜索-指纹法,三维刚性、柔性的数据库搜索,基于受体结合位点的三维数据库搜索,Chemical Informatics,UnityChemical Informatics,Unity example - 2D searching,Return all compounds in LeadScreen (50,000 compounds) with the following group,Search Takes 8 seconds and returns 84 compounds,Chemical Informatics,Unity example - 2D searchingRe,Unity example - similarity searching,Return all compounds in LeadScreen (50,000 compounds) at least 75% similar to,Search Takes 7 seconds and returns 8 compounds,Chemical Informatics,Unity example - similarity sea,Biomolecular Software,Biomolecular Software,Biopolymer（,生物大分子）,Composer（,同源模建）,MatchMaker（,穿线法）,GeneFold（,复合穿线法）,FUGUE（,远程同源模建）,ProTable（,蛋白质结构分析）,SiteID（,结合位点分析）,LeapFrog（,从头设计）,Rachel,Biomolecular SoftwareBiomolecu,生物大分子显示，修改，优化,Biopolymer,Insulin,Biomolecular Software,Sequence: FVNQHLCGSHLVEALYLVCGERGFFYTPKA,生物大分子显示，修改，优化BiopolymerInsulin,Composer（,同源模建）,生物界的共识：相似的序列决定相似的结构,根据蛋白质序列间的同源性，使用,Composer,进行同源模建,模板的结构来源于蛋白数据库（,PDB,WWW.RCSB.ORG,）,与模板的序列同源性应达到30%以上,Biomolecular Software,Composer（同源模建）Biomolecular Sof,GeneFold（,高级穿线法）,模型化所有的折叠模式，穿线法预测新蛋白质的折叠模式,序列同源性30%以下也可以进行结构预测,理论：折叠模式是有限的，新序列与模型结构的相容性决定它所采取的折叠模式。模式提取自,PDB,数据库。,Biomolecular Software,Known protein,structure,F,VNQHL,CG,SHLV,EAL,YLVCGER,GF,FYTP,KA,HYGRTSKGTPSVENIYLKFFGPMRSYLPTG,Protein,sequence,HYGRTS,K,G,TPS,V,E,NI,Y,L,KFFGPMRS,YLPTG,Predict structure,HYGRTS,K,G,TPS,V,E,NI,Y,L,KFFGPMRS,YLPTG,Align to get,score,sequence & structure,Biomolecular Software,GeneFold（高级穿线法）Biomolecular So,FUGUE（,远程同源模建）,能够通过高效率的,PSI-BLAST,搜索目标序列与数据库序列的相关性（是否归属同一个家族）。相关性决定了其结构的相容性,FUGUE,内有一个蛋白家族归类数据库。通过高效率的比对和评分矩阵，为低同源性的目标蛋白找到高质量的构建模板。,FUGUE（远程同源模建）能够通过高效率的PSI-BLAST,ProTable （,合理性分析）,Compute structure,quality data in MSS,And visualise it on,the actual structure,Biomolecular Software,ProTable （合理性分析）Compute struct,Virtual Screening,虚拟筛选,Virtual Screening,FlexX,FlexX-Pharm,Cscore,CombiFlexX,FlexS,Virtual Screening虚拟筛选Virtual,G=-RTlnK,i,基于结构的虚拟筛选,With all of its weaknesses, structure-based screening through docking is mature enough to be considered as a first-line technique in pharmaceutical discovery research。,Current opinion in chemical biology 2002 6: 439-446,对基于受体结构的虚拟筛选的评价, G=-RTlnKi基于结构的虚拟筛选With all o,成功案例,Hou T. J. Xu. X. J. Current Pharmaceutical design (In press),Target,Activity,1. Human carbonic anhydrase,0.6,nm (IC,50,),2.,AmpC,b,-lactamase,26 (,K,i,),3.,b,-adrenergic receptor kinase 1 (,b,ARK1),126 (,IC,50,),4.,Thymidalate synthase,1.4 (,K,i,),5.,Aldose reductase (ALR2),0.10 (,IC,50,),6.,Adenovirus proteinase,3.09 (,K,i,),7.,Bcl-2,10 (,IC,50,),8.,Aldose reductase,4.3 (,IC,50,),9.,Matriptase,0.92 (,IC,50,),10.,Retinoic acid receptor,2 (,ED,50,),11.,Dihydrodipicolinate reductase,7.20 (,K,i,),成功案例Hou T. J. Xu. X. J. Curren,FlexX,的优点,迅速而精确,1-3 mins per structure to dock(,迅速),gets longer with larger, more flexible ligands,Accuracy（,精确）,on its own - very good,becomes excellent when used with CScore,can be used for 1 at a time docking,for a detailed look at a few ligands,or for virtual screening（,高通量）,prioritisation of loads of structires,and we have a Linux version for really high throughput,容易使用,研究的热点,75% of my customer conversations over the last year,Virtual Screening,FlexX的优点迅速而精确Virtual Screening,工作原理,Ligand base fragment,Binding Site on Protein,One mapping of,ligand to receptor,Virtual Screening,工作原理Ligand base fragmentBindin,FlexX ,唾液酸酶,FlexX 唾液酸酶,CScore,多种评价函数共同进行打分。,G_score D_score PMF_score ChemScore,GOLD,程序,DOCK,程序*,GLIDE,程序,多种评价函数的一致性评价就是更具有参考意义的,CScore,Virtual Screening,CScoreVirtual Screening,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,糖尿病治疗,PPAR,激动剂,PPAR-基因转录因子，以配体激活方式调控脂肪细胞分化。 V,Database,Screen with DOCK,Top 1%10%,Screen with FlexX,Lead Compounds,2,Million Comps,Virtual Screening,方法,DatabaseScreen with DOCKTop 1%,PPAR,(Peroxisome proliferator-activated receptor),Large-Scale Virtual Screening,2,Million Comps.,15,years of WS,ACD-3D,Virtual Screening,MDDR,PPAR (Peroxisome proliferato,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_06,1.1010,-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,1.5210,-8,(,reference 910,-8,),Troglitazone,阳性对照药,1.5110,-5,(,reference 1.16 10,-5,),15-,d-PGJ,2,阳性对照药,3.4010,-9,(,no reference),Gi262570,K,i,常数,化合物序号,Virtual Screening,1.8810-6 DDDC_P_16 7.3510-7,PPAR,DDDC-P-06 complexes,Virtual Screening,Crystal,PPARDDDC-P-06 complexesVirtu,Molecular Diversity & Combinatorial Chemistry,Diversity and CombiChem,Legion,CombiLibMaker,DiverseSolutions,Selector,Molecular Diversity & Combinat,Legion/CombiLibMaker,builds virtual combinatorial libraries,have 2 modes of operation,core + sidechains,combine reagents,Diversity and CombiChem,+,15,diketones 31 hydrazines 465 products,Legion/CombiLibMakerDiversity,Selector - Filtering,Filter the database,Excluded/included,compounds,Filtering criteria,Diversity and CombiChem,Selector - FilteringFilter the,Descriptors,Fingerprints/Holograms,Fingerprint,presence-absence of substructural molecular fragments,Hologram,counts of substructural molecular fragments,Molecular Fragments,.,0,1,1,0,1,1,1,1,1,1,1,Molecular Fingerprint,0,5,12,0,1,8,3,5,9,10,2,Molecular Hologram,Intercompound distance from,Tanimoto or Cosine coefficients, Hamming distance,Diversity and CombiChem,DescriptorsFingerprints/Holog,Descriptors,CoMFA Fields,Co,mparative,M,olecular,F,ield,A,nalysis,Descriptors are field strengths around molecules,Steric, electrostatic, H-bond, CoMSIA, indicator, ,Fields directly encode shape & property data,Vector representation of fields compared by:,Euclidian distance,Tanimoto coefficient,Cosine coefficient,Diversity and CombiChem,DescriptorsCoMFA FieldsCompar,Selector - Diversity Selection,Distance based,must use distance based with high-dimensional metrics,example is 2D but reality is 1000D,e.g. Dissimilarity selection,Compound,Select compound at random,Pick most different compound from 1st,Pick most different compound from selected,Diversity and CombiChem,Selector - Diversity Selection,DiverseSolutions - Diversity Selection,Cell based,divide space into cells - pick a compound form each,Compound,Diversity and CombiChem,BCUT1,BCUT2,DiverseSolutions - Diversity S,Thanks!,Thanks!,