制药工程 专业英语 Unit 25

单击此处编辑母版文本样式,第二级,第三级,*,单击此处编辑母版标题样式,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,*,*,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,*,*,制药工程 专业英语 Unit 25,Words,physicochemical,pharmacological,anti,dote,anti,metabolite,anti,ulcer,leuk(a)emias (leucemias),arthritis,poliomyelitis,in vivo,/,in vitro,malignant,condescension,serendipity,paradigm,free energy/,enthalpy,/entropy,retrospective,repository,circumspect,regression analysis,CADD: Computer-Aided Drug Design,SAR: structure-activity relationship,morbidity,(mortality),a.,物理化学的，物化的,a.,药理学的,n.,解毒剂,n.,抗代谢物（药）,n.,抗胃溃疡的,n.,白血病,n.,关节炎,n.,脊髓灰质炎；小儿麻痹症,在体内,/,体外,a.,恶性的；有害的；,n.,怀恶意的人,n.,谦虚；屈尊；傲慢态度,n.,意外发现；偶然发现,n.,范例,n.,自由能,/,焓,/,熵,a.,回顾性的；怀旧的；,n.,回顾展,n.,储藏室；知识库；智囊团,a.,周到的；慎重的,回归分析,计算机辅助药物设计,构效关系,n.,发病率；致病率,(,死亡率；死亡数,),目前的药物设计,与其说是,富有成绩（成效），,不如说是,充满希望的。这意味着在最广泛意义上运用过去所认知的生物活性与物化特性之间的关系，并且希望可以预测还未合成出来的化合物在药理学的成功。,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 not yet synthesized compound can be predicted.,但目前所使用的药物很少是完全按照这种方法被发现出来。胆碱酯酶抑制剂解毒剂,吡啶肟甲基碘化物,，抗胃溃疡药,西咪替丁,，以及对抗白血病有活性的一些抗代谢药都是这样的例子。,Few drugs in use today were discovered entirely in this way. The cholinesterase inhibitor antidote,pyridine aldoxime methiodide, the antiulcer drug,Cimetidine, and some antimetabolites active against leukemias are examples.,这种方法的主要难点在于：可得的且非常复杂的预测药物作用机制的方法,既不能,预测其毒性和副作用，,也无法有助于,预料在体内药物的传输特性和代谢途径。当然，在体外产生成功治疗疗效的药物或药剂学上的细胞效应，这些都同样重要。,One of the principal difficulties in this approach is that the available and very sophisticatedmethods for predicting drug action,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.,由于对一种疾病,(,有关,),的生物学或生物化学,(,方面的知识,),基本上无知，我们最好的努力也常常遭受挫折；于是，我们就倾向于刘易斯,托马斯在他的系列精辟文章之一中，所称谓的“,不彻底的技术,”，即由于不能理解疾病的基本致病因素所采用的复杂而昂贵的疾病治疗方法。,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 “,halfway technology,” in reference to the complex and costly management of diseases whose basic causes are not understood.,而与大多数细菌性传染疾病以及甚至像脊髓灰质炎类某些病毒性疾病的治疗方案的简单性,形成鲜明对照,的是，对风湿性关节炎、大多数恶性肿瘤和全部精神类疾病的治疗都可归为此类。,The treatment of rheumatoid arthritis, most malignant tumors, and all mental diseases 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.,虽然一些,临床,药用化学家和分子药物学家一直带着一些谦虚态度和难以隐忍的急躁情绪努力从事合理的药物设计，但缓慢却有前途的发展仍不断带来希望：在该领域的进展比将生物和物理化学运用到人类和动物病理学,（所取得的进展）,快得多。计算机辅助三维药物设计的蓬勃发展有希望产生真正合理药物设计的纪元（时代）。,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 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.,直到二十世纪六十年代早期，药物设计还是基于长期经验、敏锐的观察力、意外发现、纯粹的运气、和大量艰苦工作的一种直观上的努力。发现一种临床上有效的药物的概率并不高，据估计为了生产一个具有实用（价值）的药物需要合成,3000-5000,个化合物。,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 that anywhere from 3000 to 5000 compounds were synthesized in order to produce one practical drug.,随着当今越来越严格的药品安全监管，这个（成功的）比例甚至,更小,，费用突升，也势必严重延缓新药的上市。药物研发通常所采用的经典方法是分子修饰,设计已确证活性的先导化合物的类似物。其指导原则的范例是：在分子结构中的微小改变导致其生物作用的微小、定量的变化。,With todays more strict drug safety regulations, the proportions are,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 “lead” compound. The guiding principle was the paradigm that minor changes in a molecular structure lead to minor, quantitative alterations in its biological effects.,虽然这在紧密相关的同系物中可能是正确的，但这又取决于“微小变化”的定义。将两个非常小的氢原子加入麦角碱的,8,双键上，会消除它们的子宫收缩活性；但吗啡的,N-CH,3,取代基用更大的,苯乙基,官能团替代后，则增加其活性近十倍。,Although this may be true in closely related series, it depends on the definition of minor changes, The addition of two very small hydrogen atoms to the ,8,double bond of ergot alkaloids eliminates their uterotonic activity, but replacement of the NCH,3,substituent by the large,phenethyl group,in morphine increases the activity less than ten fold.,而只将,二乙吖嗪,的侧链只用一个,C,原子进行延长竟导致,氯丙嗪,和现代精神药理学的意外发现。,1983,年就有了一篇关于经典设计的回顾性评述。,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.,从这些随机实例中可以得到两个结论。首先，在,构效关系（,SAR,）,研究中，只要其理化性质仍未被探究或其作用的分子基础仍未知，仅仅是有机分子的结构改变是毫无意义的。在有机化学概念中，结构仅仅是知识库,具有药物活性的至关重要的大量参数的载体。,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 consequences 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.,从上述实例和无数的其他例子所可以得出的第二个结论是：定性新药理作用的发现经常是基于另外的,单纯系列,药物类似物上的不连续跳跃性（发现的结果）；即使采用相当精密的方法，也很难预测。,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 methods.,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 art to a science.,尽管药物设计的经典方法取得了巨大成功，它们的不可预测性和需要付出大量的无效努力使得具有更高预测能力的更合理方法的研发极为需要，并努力使药物设计由艺术提升至科学。,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 process 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.,尽管涉及活性先导化合物的类似物的设计方法仍未改变，且药物化学家需要的专业知识仍象以前那样多；但在该方法中直观选择待合成的结构修饰的过程变得周到全面了，采用非常强大的计算机技术的基于多元回归分析的模型及模式识别方法也被应用作辅助工具。,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 promising candidates are investigated experimentally.,从大量新化合物的类似物的数据库中计算其所需的性质，比采用经典方式合成并筛选所有这些新化合物，显然要既快又便宜得多。只有有希望的候选化合物通过实验才彻底研究。,The results gained this way are incorporated into the data base, expanding and strengthening the theoretical search. Eventually, sufficient material accumulates to aid in making a confident decision about whether the “best” analogue has been prepared or whether the series should be abandoned.,采用这种方法获得的结果被并入到数据库中，拓展并增进理论研究。最终，足够的资料被积累以有助于作出确定的（或自信的）决定：是否已经制备出“最好的”类似物或是否该系列（化合物）应该被舍弃。,Although a beginning has been made, drug design is far from being either 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.,药物设计虽然已经进入了开始阶段，但还远未达到自动化或简单明了的地步。假如我们对细胞水平的分子现象基本上无知，合适的先导化合物的选择,定量药物设计的重要部分,则仍然取决于经验、偶然发现和运气。然而，目前我们至少有信心：新药的发现和现有药物的研发将能够与生物医药研究所取得的进展同步。,20,Thank you,谢谢大家！,