Williams Charles H, Hong Charles C
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; E-Mail:
Int J Mol Sci. 2011;12(4):2262-74. doi: 10.3390/ijms12042262. Epub 2011 Apr 1.
In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET) properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design.
在本文中，我们提出了一种用于合理药物设计的系统开发方法，同时回顾了该领域的行业范例、新兴技术。尽管如今计算方法的出现加速了药物开发过程，但这是一项艰巨的挑战，需要大量资源；而且往往无法产生临床上可行的结果。当前基于靶点的药物设计模式常常具有误导性，倾向于产生吸收、分布、代谢、排泄、毒理学（ADMET）性质不佳的化合物。因此，一种基于体内生物体的方法，允许对强效和选择性分子进行多学科探究，是合理药物设计的一个很好的起点。我们将回顾斑马鱼和秀丽隐杆线虫等生物体如何不仅可以作为起点，而且可以在药物开发过程的各个步骤中使用，从靶点识别到临床前试验模型。这种基于系统生物学的方法与计算生物学、遗传学和发育生物学的力量相结合，提供了一个方法框架，以避免传统基于靶点的药物设计的陷阱。
