Carmot Therapeutics, Inc. 409 Illinois Street, San Francisco, California 94158, USA.
Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA.
Nat Rev Drug Discov. 2016 Sep;15(9):605-619. doi: 10.1038/nrd.2016.109. Epub 2016 Jul 15.
After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.
经过 20 年的发展，片段药物发现（FBDD）已经从默默无闻到成为主流。有超过 30 种基于片段的候选药物进入了临床研究，其中两种已获得批准，还有几种正在进行后期试验。FBDD 在学术界和工业界都得到了广泛的应用，这从大学、非营利研究机构、生物技术公司和制药公司发表的大量论文中就可以得到证明。此外，FBDD 还借鉴了从生物化学和生物物理学到计算化学和药物化学等多个学科的知识。随着 FBDD 策略的前景变得越来越明显，现在正是汲取经验教训并为未来指明方向的好时机。本文简要讨论了如何设计片段文库，如何选择筛选技术，以及如何充分利用从这些文库中获得的信息。同时也展示了 FBDD 的概念是如何渗透并增强药物发现工作的。
