第四章、药物化学结构与生物活性的PPT参考课件.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,第四章、药物化学结构与生物活性的关系（构效关系）,分析解释药效团、药动团、毒性基团、基团变化、药效构象和手性等因素对药物发生作用的影响,1,药物作用的特异性,分子识别,分子识别是生物体实现特定功能的基本过程，在生命现象和药物作用中起中心作用,分子识别是受体与配体（底物，药物）选择性结合并产生特定功能的过程，是在超分子水平上进行信息处理的基础,分子识别是受体配体结合的推动力，分子间互补性是识别之基础。互补性包括立体形状、静电作用、氢键形成、疏水相互作用。互补结合导致系统能量的下降,2,药物作用的特异性,药物分子与靶标的相互作用是产生药效,(,包括毒性,),的分子基础,大多数药物与受体靶标的结合是非共价键作用,支配分子识别和结合的作用力分为两方面：焓作用和熵作用,3,焓,(,G,),作用,静电作用能,离子,-,离子相互作用,离子,-,偶极相互作用,偶极,-,偶极相互作用,氢键作用,诱导作用,电荷转移作用,-,正离子相互作用,4,静电作用能,离子,-,离子相互作用：相反电荷发生库仑引力：长程作用，无方向性，分子的初始识别,酸性和碱性氨基酸残基，磷酸基，胍基,水的介电常数,79,，疏水环境为,40,，蛋白质表面为,28,，蛋白质内部,4,5,静电作用能,离子,-,偶极相互作用：有方向性,作用弱于离子,-,离子相互作用,属于长程作用,金属离子与抑制剂的结合,6,静电作用能,偶极,-,偶极相互作用：广泛存在于药物与受体的作用,有方向性,7,焓,(,G,),作用,静电作用能,氢键相互作用：有方向性，氢给体和氢接受体。氢接受体为,N,和,O,原子,诱导作用,分子内电荷的的重新分布,电荷转移作用,分子间电荷的重新分布,8,熵（,S,),作用,有利的作用,有利的熵变：疏水作用。烷基与烷基相互作用，强度与烷基数成正比。,疏水固缩作用,(hydrophobic collapse),结晶态,水中,多西他赛,9,熵（,S,),作用,不利的作用,构象限制：柔性分子的构象群因与受体之结合而受限，键的旋转受阻，熵受损；,低能构象体：高能构象体,55:45 85:15 99.5:0.5 99.9:0.1,势能差值,(kJ/mol),0.42 4.2 12.6 21.9,转动和平动自由度受阻：药物被结合在受体上，失去三个平动与三个转动自由度，需要从系统的焓变得到补偿。,10,药效团概念,是药物化学和分子设计中的重要概念,化合物呈现特定生物活性所必需的原子、基团或结构片断，及其在空间的分布。,药效团是一组相同作用机理的分子所共有的结构特征。,确定药效团的程式：确定化合物的构象；确定叠合规则；找出共同特征。,药效团的应用：数据库搜寻和新分子的设计,11,药效团表示法,药效团包括：氢键给体，氢键接受体，正电中心，负电中心，疏水中心，芳环质心。,由三个特征元素构成的药效团，有三个距离约束；四个特征元素的药效团包括,6,个空间距离。,12,药效团和基本结构,13,药动团,天然氨基酸：,L-,氨基酸和二肽在体内可被主动转运,14,磷酸基,磷酸基是构成,核酸的组分，,连接药物分子,有助于向细胞,内转运。,胆酸,15,糖,糖、氨基酸和核酸是储存和携带信息的载体；,细菌和病毒感染是细胞表面识别和结合的结果；,免疫系统疾病和癌症伴随着细胞表面糖结构发生改变引起细胞调控机制出错；,糖与药物结合有特异性药理作用；,药物的糖苷较容易透入细胞，结合不同糖透入速率不同，因而产生选择性。,抗肿瘤药,16,毒性基团,环氧化物和可生成阳碳离子的基团，如芳烃、烯、炔烃、环丙基及含杂原子的类似物。,N-,氧化物、,N-,羟胺、胺类机在体内可以转化为胺的化合物,烷基硫酸酯或磺酸酯及卤代硫醚类,-,内酯及醌类,可生成阳碳离子或自由基的卤代烷，如,COCH,2,Cl,SCH,2,CH,2,Cl,N(CH,2,CH,2,Cl),2,;,含卤素的芳烃和硝基芳烃。,17,基团变化对活性的影响,酸性基团：磺酸基、磷酸基、羧基。,增加药物的水溶解性，有助于药物的摄取，有时会引起活性消失。,羧基对药物活性影响取决于他在分子中所占的比重。苯酚、水杨酸和芳乙酸类抗炎药,若羧酸的引入失去活性，则形成酯或酰胺常常恢复活性。,酰胺可以同生物大分子形成氢键多肽类药物中酰胺的氢键作用对生物活性影响较大。,碱性基团：胺、脒、胍和含氮杂环。,18,酰基,药物分子中的酰基的生物活性表现，是参与了机体或病原体的酰化反应。,有机磷农药的毒性表现在乙酰胆碱酯酶中心的丝氨酸的羟基发生了不可逆的磷酰化。,阿司匹林的乙酰基与环氧合酶中心反应，发生不可逆抑制作用。,青霉素或头孢菌素的,-,内酰胺环的酰化作用，抑制了细菌细胞壁的合成。,19,烷基,烷基的引入影响酯水分配系数,logP(,正辛醇,/,水）。直链甲基的引入增加酯溶性，支链甲基的引入，由于熵效应使分子紧缩，有利于在水中溶解。,甲基的引入可改变分子的构象。,芳环上的甲基首先被代谢氧化。,20,卤素,氟在药物修饰时很重要,键能：,C-F C-H C-Cl C-Br C-I,电负性,:F O N,，额外增加氢键。,原子半径：接近于氢，三氟甲基的体积与氯相近，对药物立体因素影响较小。,引入氯原子可增加分子的脂溶性、吸电子性的代谢阻碍。,溴和碘较少用于药物修饰，它们是好的离去基团，但苯环上的溴稳定。,21,羟基可改变药物的极性、溶解性和氢键作用,巯基由于其稳定性差和亲和性强不用作药物修饰，但可与体内离子结合，含离子的酶抑制剂改造可以应用。巯基丙醇是重金属中毒的解毒剂。,硝基是多种化疗药物的必须基团，引入硝基使得酯溶性增加，偶极矩增加，体内存留时间加长。体内易还原为氨基而发生作用。如,9-,硝基喜树碱。,22,药效构象,构象：是由于分子中单键的旋转，造成原子在空间不同的排列状态所形成的异构现象。围绕单键旋转所需的能量较小（,5 kcal/mol),结晶的分子构象是势能较低的优势构象之一，结晶构象未必是最低能量构象。,药效构象：是药物与受体分子间相互适配和诱导契切合时药物分子的构象（,pharmacophoric conformation),药效构象未必是最低能量构象。两者能量差可允许,5-7 kcal/mol,，药物与受体相互作用释放的能量足可以补偿两种构象能量差。,构象等效性：有相同作用机理的和引起相同药理或毒理效应的不同结构药物分子具有共同的药效构象。,23,乙酰胆碱药效构象的证明,证明为反式,24,三环类抗精神病药物的拓扑结构分析,25,多巴胺与受体结合的优势构象,多巴胺,Dopamine,是神经系统的重要递质，多巴胺系统功能,紊乱，引起阿次海默病、帕金森病和精神分裂等。,26,二氢吡啶拮抗剂的构象,27,连苯双酯的药效构象,28,DNA,潜入剂或干扰剂,29,DNA,潜入剂或干扰剂,抗病毒和抗癌作用：喜树碱，阿霉素，柔红霉素，连苯双酯，白叶藤碱，茶多酚，二甲胺基四环素等,有一个共平面，,根据已有活性强的改造,改变药代，减小毒性，,以茶多酚维母核计算机模拟,30,Design and Synthesis of Farnesyltransferase Inhibitors,31,Cancer Cells and Chemotherapy,Gene mutated,It results in the fundamental rules of cell behavior breaking down.,The growth of normal cells is carefully regulated to meet the needs of the whole organism;Cancer cells replicate autonomously and continuously,ultimately invading and interfering with the function of normal tissues.,Chemotherapy destroys cancer cells or slows the growth of cancer cells,32,Why Molecular Target?,There are other cells that grow fast,eg bone marrow that produce blood cells,cells in the stomach and intestines,and cells of the hair follicles.Chemotherapy also results in side effects on that tissues.,There is a need to clarify how cancers form in molecular level.We anticipate to cure cancers selectively.,33,Complicated molecular targets,Rapid development of molecular biology benefits the cancer research,but cell system is very complicated.,It is difficult to list all molecular targets,some hot targets include Gene-suppressor,Gene Transcription,Receptor Protein-Tyrosine Kinases,Metal Matrix Protein,Protesome,Ras Protein etc.,34,Function of Ras Proteins,Ras proteins function as central switches for signals by growth factors,directing cell growth,cell differentiation and other genetic programs.,Oncogenic Ras(mutated)proteins are causally implicated in a wide variety of human cancers(overall 30%incidence),including colon(90%),pancreatic(90%),breast,lung(25%),liver and renal carcinomas.,An enzyme Farnesyltransferase(FTase)plays a key role in the cell growth message transmission by Ras proteins.,35,Function of Farnesyltransferase(FTase),36,Function of Farnesyltransferase,Ras proteins locate at the inner surface of the plasma membrane and normally respond to growth stimulus of growth factors by exchanging GTP for constitutively bound GDP,thereby triggering cell division,The function of normal and oncogenic Ras proteins is dependent on the post-translational attachment of farnesyl moiety through a thioether linkage to a cycteine near the C-terminus of the protein,37,Function of Farnesyltransferase,The farnesyltransferase catalyzes the reaction of farnesyl pyrophosphate with C-terminus CAAX to form a farnesyl protein,where C stands for cysteine,A aliphatic amino acids,X serine or methionine,The reaction involves two substrates which are able to be starting points for molecular drug design,38,Crystallgraphic structure of the complex,of CAAX and FPP,CAAX,FPP,Zinc ion coordinates to nucleophilic thiol group,accelerating the reaction,CAAX mimic inhibitors should contain nucleophilic moieties,39,Found Inhibitors:CAAX Mimics,IC,50,=0.4 nM,IC,50,=0.18 nM,IC,50,=1.8 nM,IC,50,=0.79 nM,40,IC,50,=350 nM,IC,50,=42 nM,IC,50,=75 nM,FPP Analogues,An alternative approach to designing inhibitors is to imitate the structure of farnesyl pyrophosphate,41,Bisubstrate Mimics,IC,50,=33 nM,IC,50,=6 nM,IC,50,=1.0,M,Bisubstrate mimetics are transition state analogues,which strongly bind to the enzyme.The main point is to design linkers,which mimic the structure of transition state and coordinate to zinc ion,42,Compounds in Clinical Trials,Janssen R-115777,phase,Schering-Plough,SCH-66336,phase,Bristol-Myers-Squibb,BMS-214662,phase,Merk L-778123,phase,Arglabin,Registered-1999,43,CAAX mimetics,De novo Design of Target Compounds,44,Why Bezodiazepine as Scaffold?,It is called“Privilege Structure”in drug design and often used as building block in other drug research.,There are several positions in different directions that can be to used to connect pharmacophoric groups.,It possess good bioavailabity,good stability and low toxity.,45,Privilege Structure is a single molecular framework able to provide ligands for diverse receptors.Selective modification of“privilege structure”known to have provided ligands for diverse receptors in the past.,Privilege Structure,46,Bezodiazepine FTase inhibitors,47,Pharmacophore Comparison of Designed CAAX Mimetics with CAAX,hydrophobic,hydrophobic,Zn,2+,binding,Zn,2+,binding,carboxylate,48,Crystal Analysis,T14,49,Comparison of Pharmacophores Between T14 and CAAX,50,Lead compound T29,An inactive compound in antithrombin research,51,Determination of thio compound structure by Crystal analysis,52,Bisubstrate Analogues,53,S-alkyl Thiobenzoate Compounds,H,2,S,RI,H,2,O,54,Pharmacophore Comparison of Designed Bisubstrate Analogue with CAAX and FPP,55,FPP,CAAX,Pharmacophore Comparison of Designed Bisubstrate,Analogue with CAAX and FPP,56,SYNTHETIC COMPOUNDS,57,Biological Evaluation,EC,50,(,M)A549 EJ HT-29,8.05 3.05 48.57,4.00 16.40 11.03,17.82 93.54 44.86,9.85 52.90 26.01,27.29 100 86.23,Lung Bladder intestine,58,Prospect of FTase target,FTase inhibitors are undergoing clinical trials in various solid or hematological malignacies.,They can be useful in combination therapy and some clinical trials.They appear to have modest and inconstant anti-neoplastic effects,.,Not all anti-proliferative effects have been directly linked to Ras inactivation.It need more biology work to clarify the mechanism.,59,第五章、定量构效关系和计算机辅助药物设计,60,61,Rational Design Advantage,The wealth of information made available through efforts in structural genomics and advances in computation has allowed structure-based drug design to emerge as a valuable tool in medicinal chemistry.,In the past combinatorial chemistry,coupled with high-throughput approaches,shifted attention away from the more structure-based methods.,62,Large-scale determination of protein structures is reversing the drug discovery process by starting with the protein structure and using it to identify and design new ligands.,It is the integration of structure-based methods,virtual screening,and combinatorial chemistry that will provide the basis for more efficient drug design in the future,significantly reducing the time of the design cycle and the cost per marketed drug.,63,Syntheses of Tea Polyphenol Analogs as Proteasome Inhibitors,64,Twelve Natural Catechins Separated from Tea,65,Twelve Natural Catechins Separated from Tea,66,Bioactivities of Catechins,Anti-oxidants:prevention of cancer,Anti-cancer:proteasome(assembly proteins)be one of important molecular targets,Benefits on vascular diseases and heart disease,Anti-bacteria,Anti-inflammation,Regulation of gene expression in mammalian cells,Nutrition,67,68,Proteasome Function in Cell Growth,69,Electron Tomography Image,70,Three Key Function Subunits at Proteasome,1-ring(caspase-like subunit):,cut proteins and give out amino acids with acidic residues,e.g.Arginine,Lysine.,2-ring(trypsin-like subunit):,cut proteins and give out basic amino acids,e.g.Aspartic acid,Glutamic acid,5-ring(chymotrypsin-like subunit):,cut proteins and give out amino acids with hydrophobic residues,e.g.Leucine,phenylalanine,valine,Alexei F.Kisselev.,Chemistry&Biology.,2001,8,739-758.,71,Function Subunits,at 20S Proteasome,72,Catalytic Mechanism of,5-ring(Chymotrypsin-like Subunit),73,Catechins Inhibition Activities Against Proteasome,Q.Ping.Dou et al.,J Biol Chem.,2001,276,13322.,74,Mechanistic Studies,Inhibition of Proteasome by Tea Polyphenol,Above biology results:,indicate that ester bond-containing catechins showed potent inhibitions,New biology studies:,EGCG inhibition is time-dependent and irreversible,that implicate the N-terminal threonine of,5 subunit was acylated by inhibitor.,Docking method:,base on the above biology studies and crystal structure of proteasome,a docking model was set up.,David M.Smith,Tak Hang Chan,Q.Ping Dou.,Mechanistic studies and model development of tea polyphenol proteasome inhibitors:Applications to rational drug design.,manuscript.,75,What Is Docking Method,A method of molecular recognition between receptor(proteasome)and substrates(tea polyphenol)which was done in computer,1,Obtain crystal structures of proteasome and catechins (or energy minimized alternative)whose conformations were considered closed to actual pharmacophoric(binding together)conformations.,2,Find pharmacophoric(binding)groups base on biology studies and chemistry knowledge.,76,What Is Docking Method,3,Put catechin into(doing in computer)active pocket of,5 subunit,adjust the complex conformations and relative locations to match the possible,interactions.,4,Calculate the,G,changes of interactions and get the lowest energy binding model.,Use this model to predict other inhibitors activities and to analyze the inhibition mechanism(to find binding sites or pharmacophoric groups).,77,Docking Image of EGCG With Proteasome Core structure,Thr1,2.74,2.28,2.82,2.59,3.35,3.37,2.16,2.51,Ser131,Gly47,Thr21,Lys32,Met45,Ala46,Ala49,Ala20,Lys33,Val31,Ala49,Met45,3.36,4.24,3.54,3.64,3.47,A,B,C,Fig.3,78,Docking Results and Inhibition Mechanism Clarification(-)-EGCG as a sample,79,80,