制藥工程 專業(yè)英語 Unit 25

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1、會計學1制藥工程制藥工程 專業(yè)英語專業(yè)英語 Unit 25a. 物理化學的，物化的a. 藥理學的n. 解毒劑n. 抗代謝物（藥）n. 抗胃潰瘍的n. 白血病n. 關(guān)節(jié)炎n. 脊髓灰質(zhì)炎；小兒麻痹癥 在體內(nèi)/體外a. 惡性的；有害的；n. 懷惡意的人n. 謙虛；屈尊；傲慢態(tài)度n. 意外發(fā)現(xiàn)；偶然發(fā)現(xiàn)n. 范例n. 自由能/焓/熵a. 回顧性的；懷舊的；n. 回顧展n. 儲藏室；知識庫；智囊團a. 周到的；慎重的 回歸分析 計算機輔助藥物設計 構(gòu)效關(guān)系n. 發(fā)病率；致病率 (死亡率；死亡數(shù))第1頁/共20頁 目前的藥物設計與其說是富有成績（成效），不如說是充滿希望的。這意味著在最廣泛意義上運用過去

2、所認知的生物活性與物化特性之間的關(guān)系，并且希望可以預測還未合成出來的化合物在藥理學的成功。 Drug design to day is more of a hope than an achievement. It means the application of previously recognized correlations of biological activity with physicochemical characteristics in the broadest sense, in the hope that the pharmacological success of a

3、not yet synthesized compound can be predicted. 第2頁/共20頁 但目前所使用的藥物很少是完全按照這種方法被發(fā)現(xiàn)出來。膽堿酯酶抑制劑解毒劑吡啶肟甲基碘化物，抗胃潰瘍藥西咪替丁，以及對抗白血病有活性的一些抗代謝藥都是這樣的例子。 Few drugs in use today were discovered entirely in this way. The cholinesterase inhibitor antidote pyridine aldoxime methiodide, the antiulcer drug Cimetidine, and

4、 some antimetabolites active against leukemias are examples.第3頁/共20頁 這種方法的主要難點在于：可得的且非常復雜的預測藥物作用機制的方法既不能預測其毒性和副作用，也無法有助于預料在體內(nèi)藥物的傳輸特性和代謝途徑。當然，在體外產(chǎn)生成功治療療效的藥物或藥劑學上的細胞效應，這些都同樣重要。 One of the principal difficulties in this approach is that the available and very sophisticatedmethods for predicting drug ac

5、tion cannot foretell toxicity and side effects, nor do they help in anticipating the transport characteristics or metabolic fate of the drug in vivo. These are, of course, as important in producing a therapeutically successful drug in vitro or cellular effect of the pharmacy.第4頁/共20頁 由于對一種疾病(有關(guān))的生物學

6、或生物化學(方面的知識)基本上無知，我們最好的努力也常常遭受挫折；于是，我們就傾向于劉易斯托馬斯在他的系列精辟文章之一中，所稱謂的“不徹底的技術(shù)”，即由于不能理解疾病的基本致病因素所采用的復雜而昂貴的疾病治療方法。 Very often our best efforts are frustrated by basic ignorance of the biology or biochemistry underlying a disease, and we are reduced to what Lewis Thomas, in one of his incisive essays, calls

7、 “halfway technology” in reference to the complex and costly management of diseases whose basic causes are not understood. 第5頁/共20頁 而與大多數(shù)細菌性傳染疾病以及甚至像脊髓灰質(zhì)炎類某些病毒性疾病的治療方案的簡單性形成鮮明對照的是，對風濕性關(guān)節(jié)炎、大多數(shù)惡性腫瘤和全部精神類疾病的治療都可歸為此類。 The treatment of rheumatoid arthritis, most malignant tumors, and all mental diseases

8、falls into this category, and contrasts glaringly with the simplicity of dealing with most infectious diseases of bacterial origin and even some viral diseases like poliomyelitis.第6頁/共20頁 雖然一些臨床藥用化學家和分子藥物學家一直帶著一些謙虛態(tài)度和難以隱忍的急躁情緒努力從事合理的藥物設計，但緩慢卻有前途的發(fā)展仍不斷帶來希望：在該領(lǐng)域的進展比將生物和物理化學運用到人類和動物病理學（所取得的進展）快得多。計算機輔助

9、三維藥物設計的蓬勃發(fā)展有希望產(chǎn)生真正合理藥物設計的紀元（時代）。 Although some practicing medicinal chemists and molecular pharmacologists still regard efforts at rational drug design with some condescension and ill-concealed impatience, a slow rapid but promising development gives renewed hope that progress in this area will not

10、be less than in the application of biology and physical chemistry to human and animal pathology. The explosive development of computer-aided drug design in three dimensions promises to lead to the era of true rational drug design.第7頁/共20頁 直到二十世紀六十年代早期，藥物設計還是基于長期經(jīng)驗、敏銳的觀察力、意外發(fā)現(xiàn)、純粹的運氣、和大量艱苦工作的一種直觀上的努力。

11、發(fā)現(xiàn)一種臨床上有效的藥物的概率并不高，據(jù)估計為了生產(chǎn)一個具有實用（價值）的藥物需要合成3000-5000個化合物。 Until the early 1960s, drug design was an intuitive endeavor based on long experience, keen observation, serendipity, sheer luck, and a lot of hard work. The probabilities of finding a clinically useful drug were not good; it was estimated th

12、at anywhere from 3000 to 5000 compounds were synthesized in order to produce one practical drug. 第8頁/共20頁 隨著當今越來越嚴格的藥品安全監(jiān)管，這個（成功的）比例甚至更小，費用突升，也勢必嚴重延緩新藥的上市。藥物研發(fā)通常所采用的經(jīng)典方法是分子修飾設計已確證活性的先導化合物的類似物。其指導原則的范例是：在分子結(jié)構(gòu)中的微小改變導致其生物作用的微小、定量的變化。 With todays more strict drug safety regulations, the proportions are

13、even worse and the costs skyrocket, retarding the introduction of new drugs to a dangerous extent. The classical method usually applied in drug development was molecular modificationthe design of analogues of a proven active “l(fā)ead” compound. The guiding principle was the paradigm that minor changes

14、in a molecular structure lead to minor, quantitative alterations in its biological effects. 第9頁/共20頁 雖然這在緊密相關(guān)的同系物中可能是正確的，但這又取決于“微小變化”的定義。將兩個非常小的氫原子加入麥角堿的8雙鍵上，會消除它們的子宮收縮活性；但嗎啡的N-CH3取代基用更大的苯乙基官能團替代后，則增加其活性近十倍。 Although this may be true in closely related series, it depends on the definition of minor c

15、hanges, The addition of two very small hydrogen atoms to the 8 double bond of ergot alkaloids eliminates their uterotonic activity, but replacement of the NCH3 substituent by the large phenethyl group in morphine increases the activity less than ten fold. 第10頁/共20頁 而只將二乙吖嗪的側(cè)鏈只用一個C原子進行延長竟導致氯丙嗪和現(xiàn)代精神藥理

16、學的意外發(fā)現(xiàn)。1983年就有了一篇關(guān)于經(jīng)典設計的回顧性評述。 Extension of the side chain of diethazine by only one carbon atom led to the serendipitous discovery of Chlorpromazine and modern psychopharmacology. A retrospective account of classical drug design was provided in 1983.第11頁/共20頁 從這些隨機實例中可以得到兩個結(jié)論。首先，在構(gòu)效關(guān)系（SAR）研究中，只要其理化

17、性質(zhì)仍未被探究或其作用的分子基礎仍未知，僅僅是有機分子的結(jié)構(gòu)改變是毫無意義的。在有機化學概念中，結(jié)構(gòu)僅僅是知識庫具有藥物活性的至關(guān)重要的大量參數(shù)的載體。 There are two conclusions to be drawn from these random examples. First, a merely structural change in an organic molecule is meaningless in structure-activity relationship (SAR) studies as long as its physicochemical conse

18、quences remain unewplored and the molecular basis of its action remains known. Structure, in the organic chemical sense, is only a repository, a carrier of numerous parameters of vital importance of drug activity.第12頁/共20頁 從上述實例和無數(shù)的其他例子所可以得出的第二個結(jié)論是：定性新藥理作用的發(fā)現(xiàn)經(jīng)常是基于另外的單純系列藥物類似物上的不連續(xù)跳躍性（發(fā)現(xiàn)的結(jié)果）；即使采用相當精密

19、的方法，也很難預測。 The second conclusion to be drawn from the above examples and innumerable others is that the discovery of qualitatively new pharmacological effects is often a discontinuous jump in an otherwise monotonous series of drug analogues and is hard to predict, even with fairly sophisticated meth

20、ods.第13頁/共20頁 Despite the great success of the classical methods of drug design, their unpredictability and the tremendous amount of wasted effort expended have necessitated the development of more rational methods with a much higher predictive capability, in an effort to elevate drug design from an

21、 art to a science. 盡管藥物設計的經(jīng)典方法取得了巨大成功，它們的不可預測性和需要付出大量的無效努力使得具有更高預測能力的更合理方法的研發(fā)極為需要，并努力使藥物設計由藝術(shù)提升至科學。第14頁/共20頁 The approach involving the design of analogues of an active lead compound remains unchanged, and the expertise of the medicinal chemist is as much in demand as ever; however, the intuitive pr

22、ocess of selecting structural modifications for synthesis becomes circumspect in this approach, and models based on multiple regression analysis and pattern recognition methods, using very powerful computer techniques, are employed as aids. 盡管涉及活性先導化合物的類似物的設計方法仍未改變，且藥物化學家需要的專業(yè)知識仍象以前那樣多；但在該方法中直觀選擇待合成

23、的結(jié)構(gòu)修飾的過程變得周到全面了，采用非常強大的計算機技術(shù)的基于多元回歸分析的模型及模式識別方法也被應用作輔助工具。第15頁/共20頁 It is obviously much faster and cheaper to calculate the required properties of novel compounds from a large pool of data on their analogues than to synthesize and screen all such new, compounds in the classical fashion. Only promisi

24、ng candidates are investigated experimentally. 從大量新化合物的類似物的數(shù)據(jù)庫中計算其所需的性質(zhì)，比采用經(jīng)典方式合成并篩選所有這些新化合物，顯然要既快又便宜得多。只有有希望的候選化合物通過實驗才徹底研究。第16頁/共20頁 The results gained this way are incorporated into the data base, expanding and strengthening the theoretical search. Eventually, sufficient material accumulates to a

25、id in making a confident decision about whether the “best” analogue has been prepared or whether the series should be abandoned. 采用這種方法獲得的結(jié)果被并入到數(shù)據(jù)庫中，拓展并增進理論研究。最終，足夠的資料被積累以有助于作出確定的（或自信的）決定：是否已經(jīng)制備出“最好的”類似物或是否該系列（化合物）應該被舍棄。第17頁/共20頁 Although a beginning has been made, drug design is far from being eith

26、er automatic or foolproof. The choice of proper lead compounda necessity in quantitative drug designis still based on experience, serendipity, and luck, given our basic ignorance of molecular phenomena at the cellular level. Now, however, we can at least have the confidence that the discovery of new drugs and the development of existing ones will be able to keep pace with the progress of biomedical research. 藥物設計雖然已經(jīng)進入了開始階段，但還遠未達到自動化或簡單明了的地步。假如我們對細胞水平的分子現(xiàn)象基本上無知，合適的先導化合物的選擇定量藥物設計的重要部分則仍然取決于經(jīng)驗、偶然發(fā)現(xiàn)和運氣。然而，目前我們至少有信心：新藥的發(fā)現(xiàn)和現(xiàn)有藥物的研發(fā)將能夠與生物醫(yī)藥研究所取得的進展同步。第18頁/共20頁20第19頁/共20頁