Metabolic analysis in drug design
Metabolic analysis in drug design
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DOI：
10.1016/s1631-0691(03)00117-3
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发表时间：
2003-05-01
影响因子：
2
通讯作者：
Cárdenas, ML
中科院分区：
文献类型：
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作者：
Cornish-Bowden, A;Cárdenas, ML
生物技术经常被认为过去20年的进步代表着巨大的成功，但现实却截然不同。例如。1935年至1963年间，人们发现了十大类抗生素，但在1963年之后，只发现了一种。恶唑烷酮。为了说明通过考虑新陈代谢系统的真实行为来做得更好的可能性。我们可以研究人们如何改变细胞中一种酶的活性(例如，通过基因操作，或通过抑制物的作用等)。为了达到技术目的。例如，如果目标是消灭害虫，人们可能会认为抑制剂的作用可能是将必要的通量抑制到不足以维持生命的水平，或者将中间体的浓度提高到有毒的水平。前者可能看起来更明显，但后者在实践中更容易实现，而且有一些以这种方式工作的工业产品的优秀例子，如除草剂农达和奎宁类的抗疟疾药物。一项对布鲁氏锥虫(引起非洲昏睡病的寄生虫)糖酵解的研究表明，要使这种方法发挥作用，所选的目标酶必须具有不受化学计量限制的浓度的底物。这在一个复杂的系统中不一定很容易找到，通常需要在计算机中分析新陈代谢网络。(C)2003年科学院。由爱思唯尔爱思唯尔公司出版。版权所有。
Biotechnology is often presented as if progress in the past two decades represented a major success, but the reality is quite different. For example. ten major classes of antibiotics were discovered between 1935 and 1963, but after 1963 there has been just one. the oxazolidones. To illustrate the possibilities of doing better by taking account of the real behaviour of metabolic systems. we can examine how one might modify the activity of an enzyme in the cell (for example by genetic manipulation, or by the action of an inhibitor, etc.) to satisfy a technological aim. For example, if the objective is to eliminate a pest, one might suppose that the effect of an inhibitor could be to depress an essential flux to a level insufficient for life, or to raise the concentration of an intermediate to a toxic level. The former may seem the more obvious, but the latter is easier to achieve in practice, and there are some excellent examples of industrial products that work in that way, such as the herbicide 'Roundup' and antimalarials of the quinine class. A study of glycolysis in the parasite Trypanosoma brucei (which causes African sleeping sickness) indicates that for this approach to work the selected target enzyme must have a substrate with a concentration that is not limited by stoichiometric constraints. That is not necessarily easy to find in a complicated system, and typically needs the metabolic network to be analysed in the computer. (C) 2003 Academie des sciences. Published by Editions scientifiques et medicales Elsevier SAS. All rights reserved.