Caporale L H
Merck Research Laboratories, Rahway, NJ 07065.
Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):75-82. doi: 10.1073/pnas.92.1.75.
Biological diversity reflects an underlying molecular diversity. The molecules found in nature may be regarded as solutions to challenges that have been confronted and overcome during molecular evolution. As our understanding of these solutions deepens, the efficiency with which we can discover and/or design new treatments for human disease grows. Nature assists our drug discovery efforts in a variety of ways. Some compounds synthesized by microorganisms and plants are used directly as drugs. Human genetic variations that predispose to (or protect against) certain diseases may point to important drug targets. Organisms that manipulate molecules within us to their benefit also may help us to recognize key biochemical control points. Drug design efforts are expedited by knowledge of the biochemistry of a target. To supplement this knowledge, we screen compounds from sources selected to maximize molecular diversity. Organisms known to manipulate biochemical pathways of other organisms can be sources of particular interest. By using high throughput assays, pharmaceutical companies can rapidly scan the contents of tens of thousands of extracts of microorganisms, plants, and insects. A screen may be designed to search for compounds that affect the activity of an individual targeted human receptor, enzyme, or ion channel, or the screen might be designed to capture compounds that affect any step in a targeted metabolic or biochemical signaling pathway. While a natural product discovered by such a screen will itself only rarely become a drug (its potency, selectivity, bioavailability, and/or stability may be inadequate), it may suggest a type of structure that would interact with the target, serving as a point of departure for a medicinal chemistry effort--i.e., it may be a "lead." It is still beyond our capability to design, routinely, such lead structures, based simply upon knowledge of the structure of our target. However, if a drug discovery target contains regions of structure homologous to that in other proteins, structures known to interact with those proteins may prove useful as leads for a medicinal chemistry effort. The specificity of a lead for a target may be optimized by directing structural variation to specificity-determining sites and away from those sites required for interaction with conserved features of the targeted protein structure. Strategies that facilitate recognition and exploration of sites at which variation is most likely to generate a novel function increase the efficiency with which useful molecules can be created.
生物多样性反映了潜在的分子多样性。自然界中发现的分子可被视为在分子进化过程中所面临并克服的挑战的解决方案。随着我们对这些解决方案的理解不断深入，我们发现和/或设计人类疾病新疗法的效率也在提高。大自然以多种方式助力我们的药物发现工作。微生物和植物合成的一些化合物可直接用作药物。易患（或预防）某些疾病的人类基因变异可能指向重要的药物靶点。那些利用我们体内分子为自身谋利的生物体也可能帮助我们识别关键的生化控制点。对靶点生物化学的了解有助于加快药物设计工作。为补充这方面的知识，我们从经过挑选以最大化分子多样性的来源中筛选化合物。已知能操纵其他生物体生化途径的生物体可能是特别值得关注的来源。通过使用高通量检测方法，制药公司可以快速扫描数以万计的微生物、植物和昆虫提取物的成分。筛选可能旨在寻找影响单个靶向人类受体、酶或离子通道活性的化合物，或者筛选可能旨在捕获影响靶向代谢或生化信号通路中任何步骤的化合物。虽然通过这种筛选发现的天然产物本身很少能成为药物（其效力、选择性、生物利用度和/或稳定性可能不足），但它可能提示一种与靶点相互作用的结构类型，作为药物化学研究的出发点——即它可能是一个“先导物”。仅基于对靶点结构的了解，我们仍无法常规地设计出这样的先导结构。然而，如果药物发现靶点包含与其他蛋白质中结构同源的区域，已知与那些蛋白质相互作用的结构可能被证明可作为药物化学研究的先导物。通过将结构变异导向特异性决定位点并远离与靶向蛋白质结构保守特征相互作用所需的位点，可以优化先导物对靶点的特异性。有助于识别和探索最有可能产生新功能的变异位点的策略，可提高创造有用分子的效率。
