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1、藥物設計Drug Design尚魯慶南開大學藥學院Enzyme based drug design Target Based Drug DesignNucleic acid based drug design Signal transduction drug design Ion channel based drug design Nucleic Acid Based Drug Design Nucleic AcidRNADNANucleic AcidBiosynthesis of Ribonucleic Acid 一、Synthesis of Purin NucleotidePRPP的生物合

2、成及其氨基化 What is de novo synthesis?Biosynthesis of IMP從IMP轉化成AMP和GMP的生物合成途徑 AMPGMPBiosynthesis of AMP and DMPUMPBiosynthesis of Ribonucleic Acid 二、Synthesis of Pyrimidine NucleotidePurine AnaloguesPyrimidine Analogues治療實體瘤的抗腫瘤藥物缺乏選擇性,為CNS, 胃腸道等方面帶來毒性Pyrimidine AnaloguesPyrimidine AnaloguesAs the drug

3、to therapy acute myeloblastic leukemia 急性粒細胞白血病 Pyrimidine AnaloguesDihyrofolate Reductase(DHFR) InhibitorSupercoiledDNADNA GyrasePteridine+PABA二氫葉酸還原酶二氫蝶酸合成酶嘌呤嘧啶二氫蝶酸四氫葉酸二氫葉酸RelaxedDNAAMT, MTX-COOHNH2-磺胺類Dihyrofolate Reductase(DHFR)二氫葉酸還原酶二氫葉酸還原酶 InhibitorDihyrofolate Reductase(DHFR) InhibitorAMT an

4、d MTX: DHFR inhibitors, used as anticancer drugs Crystal structure of DHFR and MTX complexDihyrofolate Reductase(DHFR) InhibitorEDX and PDX exhibit better potency than AMT and MTX, overcome the Drug-resistance of AMT and MTX GARFTGARFT,glycinamide ribonucliotide formyltransferase, is a critical enzy

5、me involved in purine biosynthesis. Its central role in folate metabolism has made it an obvious target for the development of GARFT inhibitors, primarily for oncology.GARFT InhibitorsThe first clinically used GARFT inhibitor as anticancer drug.GARFT InhibitorsGARFT InhibitorssiRNAHow does an siRNA

6、Work?What an siRNA look like?siRNA gene silencing:A new therapeutic modality First new biological modality since discovery of protein therapeutics Applicable across many diseases Ability to reduce level of any protein target of interest, including those involved in protein-protein interactions Poten

7、tial to shorten discovery-to-development time Launched siRNA therapeutics program through collaboration with Alnylam (Fall 2005)siRNA and shRNAPromising, but not much experience yetTarget space: Almost anything, including all of above + transcription factors Reduces protein concentration use for tar

8、gets where this will helpOpportunities: Idea limited? May allow control of transcriptional outputHurdles on way to clinic: Potency and specificity, physicochemical properties, PK / ADME, toxicology / side effects (off- and on-target), other Delivery not all tissues accessible at present Every molecu

9、le is likely to be different in terms of sequence effects May be common chemical properties of class, but no experience yetSignal Transduction Based Drug DesignInformation and SignalInformation: 信息, 與“不確定”相聯(lián)系 信息是認識主體(人、生物、機器)所感受的或所表達的事物運動的狀態(tài)和運動狀態(tài)變化的方式。信息的特征為:(1) 接收者在收到信息之前,對它的內(nèi)容是不知道的,所以信息是新知識、新內(nèi)容。(2

10、) 信息是能使認識某一事物的未知性或不確定性減少的有用知識(3) 信息可以產(chǎn)生,也可以消失,同時信息可以被攜帶、貯存及處理(4) 信息是可以量度的,信息量有多少的差別。 Signal:信號, 信息的載體,包括小分子和大分子化合物,也有物理因素(生物電,溫度等)。 1、生物大分子的結構信號:蛋白質、多糖、核酸的結構信息 2、化學信號:細胞間通訊的信號分子:激素、神經(jīng)遞質與神經(jīng)肽、局部化學介導因子、抗體、淋巴因子 細胞內(nèi)通訊的信號分子 :cAMP, cGMP, Ca2+, IP3, DG、NO3、物理信號:電、光、磁 Signal molecules between cellsSignal mol

11、ecules between cells 類別名稱 分泌部位 組成 主要作用含氮類氨基酸衍生物腎上腺素腎上腺髓質兒茶酚胺(仲)增加血壓、心率,糖原分解去甲腎上腺素腎上腺髓質兒茶酚胺(伯)甲狀腺素(T4)甲狀腺含碘酩氨酸衍生物增加代謝(廣譜)小肽類促甲狀腺素釋放因子(TRH)下丘腦3肽刺激垂體前葉分泌促甲狀腺素促性腺素釋放因子(GnRH)下丘腦10肽刺激垂體前葉分泌促性腺素生長激素釋放抑制素(SRIH)下丘腦14肽抑制垂體前葉分泌生長激素加壓素(ADH)下丘腦14肽增加血壓蛋白質類促腎上腺皮質激素釋放因子(CRH)下丘腦41個氨基酸刺激垂體前葉分泌促腎上腺素生長素(GH)腦垂體前葉191個氨基酸

12、 刺激肝臟生成生長調節(jié)素,促肌肉骨骼生長胰島素胰島細胞雙鏈,51個氨基酸糖的利用,刺激蛋白質、脂肪合成甲狀旁腺激素(P TH)甲狀旁腺84個氨基酸調節(jié)鈣、鎂和磷酸根離子表皮生長因子小鼠鄂下腺53個氨基酸刺激上皮等細胞分裂糖蛋白促卵泡激素(F SH)腦垂體前葉雙鏈,210個氨基酸刺激雌二醇分泌促黃體激素(LH)腦垂體前葉雙鏈,207個氨基酸刺激卵母細胞成熟及分泌孕酮促甲狀腺激素(T SH)腦垂體前葉雙鏈,204個氨基酸刺激甲狀腺分泌甾類雌二醇卵巢膽固醇衍生物促雌性器官發(fā)育成熟黃體(孕)酮卵巢黃體17個碳原子組成增加子宮血液,減少子宮收縮睪酮睪丸促雄性器官發(fā)育成熟皮質醇腎上腺皮質影響蛋白質、糖、脂

13、代謝,增加免疫能力皮質酮腎上腺皮質影響蛋白質、糖、脂代謝醛固酮腎上腺皮質調節(jié)水分與離子平衡1、合成2、信號細胞釋放信號分子3、信號分子運輸?shù)桨屑毎?、通過特定受體蛋白的信號檢測5、細胞內(nèi)由受體-信號復合體觸發(fā)的代謝、功能和發(fā)育的改變6、信號的消除,終止細胞響應Signal transduction pathwaySignal molecule, a chemical involved in transmitting information between cells.Signal transduction pathwayReceptor細胞表面或亞細胞組分中的一種分子,可以識別并特異地與有生物

14、活性的化學信號物質(配體)結合,從而激活或啟動一系列生物化學反應,最后導致該信號物質特定的生物效應Function of receptor: 1、識別特異的配體; 2、把識別和接受的信號準確無誤的放大并傳遞到細胞內(nèi)部,產(chǎn)生特定的細胞反應。Classification of receptorn細胞表面受體:G蛋白耦聯(lián)受體家族:腎上腺素受體、多巴受體、視紫紅蛋白酪氨酸激酶受體家族:多數(shù)生長因子受體(如IGF,EGF,PDGF,NGF,SCF,HGF等生長因子的受體),除胰島素受體外,這類受體均由一條肽鏈組成細胞因子受體家族:干擾素受體。離子通道受體:神經(jīng)突觸,如ACH,5-HT受體n胞內(nèi)受體或核受

15、體:甾體類激素受體Classification of receptorG-protein: 是一種鳥苷酸結合蛋白,是由、和三個亞基組成的異三聚體,和亞基總是緊密結合在一起作為一個功能單位GG protein coupled receptor (GPCR)G protein coupled receptor (GPCR) GPCR, also known as seven-transmembrane domain receptors, comprise a large protein family of transmembrane receptors that sense molecules o

16、utside the cell and activate inside signal transduction pathways and, ultimately, cellular responses.GPCR and Signal transductionGPCR and Signal transductionLimitation for GPCR research Crystal structure: So far four different GPCR structures have been determined by X-ray crystallography: 2 Adrenerg

17、ic Receptor, 1 Adrenergic Receptor, Adenosine Receptor, Rhodopsin 受體受體G蛋白蛋白酶和離子通道酶和離子通道第二信使第二信使組織分布組織分布功能功能a a1Gq 磷脂酶磷脂酶C DAG IP3血管及泌尿生殖系血管及泌尿生殖系平滑肌平滑肌收縮收縮Gq 磷脂酶磷脂酶D肝臟肝臟糖元生成,糖異生糖元生成,糖異生Gq, Gi / Go 磷脂酶磷脂酶A2腸道平滑肌腸道平滑肌超極化,松弛超極化,松弛Gq? Ca2+通道通道心臟心臟增強收縮力,心率加快增強收縮力,心率加快a a2Gi 1, 2, or 3 腺苷酸環(huán)化酶腺苷酸環(huán)化酶 cAMP胰島

18、胰島b b細胞細胞減少胰島素分泌減少胰島素分泌Gi (bb subunits) K+通道通道血小板血小板聚集聚集Go Ca2+通道(通道(L-和和N-型)型)神經(jīng)末梢神經(jīng)末梢減少減少NE分泌分泌? PLC, PLA2血管平滑肌血管平滑肌收縮收縮b b1Gs 腺苷酸環(huán)化酶腺苷酸環(huán)化酶 cAMP心臟心臟增強收縮力,加快心率增強收縮力,加快心率 L-型型Ca2+通道通道腎小球旁細胞腎小球旁細胞增加腎素分泌增加腎素分泌b b2Gs 腺苷酸環(huán)化酶腺苷酸環(huán)化酶 cAMP平滑肌平滑肌松弛松弛骨骼肌骨骼肌糖元生成,糖元生成,K+攝取攝取肝臟肝臟糖元生成,糖異生糖元生成,糖異生b b3Gs 腺苷酸環(huán)化酶腺苷酸環(huán)

19、化酶 cAMP脂肪細胞脂肪細胞脂肪分解脂肪分解Adrenergic Receptor subtypes腎上腺素腎上腺素去甲腎上腺素去甲腎上腺素麻黃堿麻黃堿多巴胺多巴胺去氧腎上腺素去氧腎上腺素間羥胺間羥胺奧克巴胺奧克巴胺昔奈福林昔奈福林甲氧明甲氧明甲氧那明甲氧那明甲基多巴甲基多巴阿可樂定阿可樂定可樂定可樂定羥甲唑啉羥甲唑啉受體激動劑受體激動劑和和受體受體1和和2受受體體1受體受體2受體受體GPCR based drug (Adrenergic Receptor Agonist )受體激動劑受體激動劑1和和2受體受體1受體受體2受體受體異丙腎上腺素異丙腎上腺素沙丁胺醇沙丁胺醇乙諾那林乙諾那林普羅托

20、醇普羅托醇多巴酚丁胺多巴酚丁胺普瑞特羅普瑞特羅依替福林依替福林特布他林特布他林克侖特羅克侖特羅GPCR based drug (Adrenergic Receptor Agonist )GPCR based drug (Adrenergic Receptor Agonist )a1 receptor agonist 去氧腎上腺素間羥胺昔奈福林 酚羥基使活性增強,酚羥基使活性增強,3-,4-位羥基最明顯位羥基最明顯以其他環(huán)狀結構代以其他環(huán)狀結構代替苯環(huán),外周作用仍替苯環(huán),外周作用仍保留,但中樞興奮作保留,但中樞興奮作用降低用降低-C上通常帶上通常帶-OH,以以R構型為活性構型構型為活性構型N上以

21、取代對上以取代對和和受體效應受體效應的相對強弱有顯著影響。的相對強弱有顯著影響。 由由甲基到叔丁基,甲基到叔丁基,受體效應減受體效應減弱,弱, 受體效應增強,且對受體效應增強,且對2受體選擇性也提高受體選擇性也提高-C上若帶有一個上若帶有一個-CH3,外,外周擬腎上腺素作用減弱,中樞周擬腎上腺素作用減弱,中樞興奮作用增強,作用時間延長興奮作用增強,作用時間延長以兩個碳原子的長度為最佳,碳鏈以兩個碳原子的長度為最佳,碳鏈延長或縮短均使作用降低延長或縮短均使作用降低SAR of adrenergic receptor agonistGPCR based drug (Adrenergic Recep

22、tor Agonist )NCH3HHCH2COHHOHOHX陰離子部位受體未接觸部位平面區(qū)XNCH3HHCH2CHOHOHOH陰離子部位受體平面區(qū)GPCR based drug (Adrenergic Receptor Agonist )S-epinephrine R-epinephrine Second messenger cAMPcGMPIP3 and DAGCa2+NOcAMP based drug design選擇性作用于依賴cAMP的蛋白激酶II的調節(jié)亞基,誘導腫瘤細胞分化用于心絞痛及心肌梗死的治療cAMP based drug designAdenylate cyclase: t

23、he enzyme that synthesizes cAMP from ATP Phosphodiesterase (PDE):The enzyme catalyzes cAMP to 5AMP. A big family comprises of subtypes (PDE1-PDE11),and show desired druglikepropertiesPhosphodiesterase inhibitor (PDEI)非選擇性PDEI作用增加20倍作用增加100倍,且有興奮b-受體作用軟化紅細胞,激活腦代謝擴張腦血管,改善記憶Phosphodiesterase inhibitor

24、(PDEI)Ion Channel Based Drug DesignIon Channel Ion channel are membrane complexes and their function is to facilitate the diffusion of ions across the cell membrane. 1 - channel domains, 2 - outer vestibule, 3 - selectivity filter, 4 - diameter of selectivity filter, 5 - phosphorylation site, 6 - ce

25、ll membraneIon ChannelPeter AgreRoderick MacKinnonThe Nobel Prize in Chemistry 2003 was awarded for discoveries concerning channels in cell membranes“Birth of an idea”Ion ChannelsChloride channelsDiversity of Ion ChannelPotassium channelsSodium channelsCalcium channelsProton channelsNonselective cat

26、ionchannelsCalcium Channeln An ion channel displays selectivepermeability to calcium ion.nComposes of different subtypes: T, L, N, P, Q, R and so on. n Related to the heart muscle control.Calcium Channel BlockersA calcium channel blocker is a chemical that disrupts the movement of calcium (Ca2+) thr

27、ough calcium channels. Calcium channel blockers blockthe inward movement of calciumby binding to the L-type calcium channels in the heart and insmooth muscle of the peripheralvasculature.AmlodipineCalcium Channel BlockersCalcium Channel Blockers3,5-位取代酯基不同,位取代酯基不同,為手性中心,酯基大小為手性中心,酯基大小對活性影響不大,不對對活性影響

28、不大,不對稱酯基影響作用部位稱酯基影響作用部位活性:苯基或取代活性:苯基或取代苯基苯基 環(huán)烷基環(huán)烷基 甲基甲基 H活性必需,變?yōu)檫拎きh(huán)活性必需,變?yōu)檫拎きh(huán)或六氫吡啶環(huán)均無活性或六氫吡啶環(huán)均無活性活性必需,若為乙?;钚员匦?,若為乙?;蚯杌钚越档?,若為硝或氰基活性降低,若為硝基則激活鈣離子通道基則激活鈣離子通道鄰、間位有吸電子基團鄰、間位有吸電子基團時活性較佳,對位取代活時活性較佳,對位取代活性下降性下降Calcium Channel BlockersHypertension高血壓Angina pectoris心絞痛Potassium ChannelPotassium channels ar

29、e the most widely distributed type of ion channel and are found in virtually all living organisms.Potassium channels have a tetrameric structure in which four identical protein subunits associate to form a fourfold symmetric (C4) complex arranged around a central ion conducting pore play critical roles in cellular signaling processes regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithel

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