Guo Zong-ru
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
Yao Xue Xue Bao. 2008 Sep;43(9):898-904.
Hits, leads and drug candidates constitute three millstones in the course of drug discovery and development. The definition of drug candidates is a critical point in the value chain of drug innovation, which not only differentiates the research and development stages, but more importantly, determines the perspective and destiny of the pre-clinical and clinical studies. All outcomes from the development stage are actually attributed to the chemical structure of candidates. The quality of candidates, however, is restricted by the drug-likeness of lead compounds, which in turn is decided by the characteristics of hits. The hit-to-lead is to provide a promising and druggable structure for further development, whereas the optimization of lead compounds is a process to transform an active compound into a drug, which in essence is molecular manipulation in multi-dimensional space related to pharmacodynamic, pharmacokinetic, physico-chemical, and safety properties. This review discusses the strategic principles in hit discovery, lead identification and optimization, as well as drug candidate definition with practical examples.
命中化合物、先导化合物和药物候选物是药物发现与开发过程中的三块试金石。药物候选物的定义是药物创新价值链中的一个关键点，它不仅区分了研发阶段，更重要的是，决定了临床前和临床研究的方向与命运。开发阶段的所有成果实际上都归因于候选物的化学结构。然而，候选物的质量受到先导化合物类药性的限制，而先导化合物的类药性又由命中化合物的特性决定。从命中化合物到先导化合物是为进一步开发提供一个有前景且可成药的结构，而先导化合物的优化是将活性化合物转化为药物的过程，其实质是在与药效学、药代动力学、物理化学和安全性相关的多维空间中进行分子操作。本文通过实例讨论了命中化合物发现、先导化合物识别与优化以及药物候选物定义中的战略原则。
