Lee Jonathan A, Berg Ellen L
1Quantitative and Structural Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
J Biomol Screen. 2013 Dec;18(10):1143-55. doi: 10.1177/1087057113506118. Epub 2013 Sep 30.
Innovation and new molecular entity production by the pharmaceutical industry has been below expectations. Surprisingly, more first-in-class small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) between 1999 and 2008 were identified by functional phenotypic lead generation strategies reminiscent of pre-genomics pharmacology than contemporary molecular targeted strategies that encompass the vast majority of lead generation efforts. This observation, in conjunction with the difficulty in validating molecular targets for drug discovery, has diminished the impact of the "genomics revolution" and has led to a growing grassroots movement and now broader trend in pharma to reconsider the use of modern physiology-based or phenotypic drug discovery (PDD) strategies. This "From the Guest Editors" column provides an introduction and overview of the two-part special issues of Journal of Biomolecular Screening on PDD. Terminology and the business case for use of PDD are defined. Key issues such as assay performance, chemical optimization, target identification, and challenges to the organization and implementation of PDD are discussed. Possible solutions for these challenges and a new neoclassic vision for PDD that combines phenotypic and functional approaches with technology innovations resulting from the genomics-driven era of target-based drug discovery (TDD) are also described. Finally, an overview of the manuscripts in this special edition is provided.
制药行业的创新和新分子实体生产一直未达预期。令人惊讶的是，1999年至2008年间美国食品药品监督管理局（FDA）批准的更多一类小分子药物是通过类似于基因组学前药理学的功能表型先导物生成策略鉴定出来的，而非当代分子靶向策略，尽管当代分子靶向策略涵盖了绝大多数的先导物生成工作。这一观察结果，再加上药物发现中分子靶点验证的困难，削弱了“基因组学革命”的影响，并引发了一场日益壮大的草根运动，如今制药行业出现了更广泛的趋势，即重新考虑使用基于现代生理学或表型的药物发现（PDD）策略。本“客座编辑专栏”介绍并概述了《生物分子筛选杂志》关于PDD的两部分特刊。定义了PDD的术语和商业案例。讨论了诸如检测性能、化学优化、靶点识别以及PDD组织与实施面临的挑战等关键问题。还描述了应对这些挑战的可能解决方案，以及一种将表型和功能方法与基于靶点的药物发现（TDD）基因组学驱动时代的技术创新相结合的PDD新古典主义愿景。最后，对本特刊中的稿件进行了概述。
