Drug Discovery Research, Astellas Pharma, Inc., 21 Miyukigaoka Tsukuba, Ibaraki 305-8585, Japan +81 29 863 6768 ; +81 29 856 2558 ;
Expert Opin Drug Discov. 2009 Nov;4(11):1125-44. doi: 10.1517/17460440903317580.
Fragment-based drug discovery (FBDD) has been established as a powerful alternative and complement to traditional high-throughput screening techniques for identifying drug leads. At present, this technique is widely used among academic groups as well as small biotech and large pharmaceutical companies. In recent years, > 10 new compounds developed with FBDD have entered clinical development, and more and more attention in the drug discovery field is being focused on this technique.
Under the FBDD approach, a fragment library of relatively small compounds (molecular mass = 100 - 300 Da) is screened by various methods and the identified fragment hits which normally weakly bind to the target are used as starting points to generate more potent drug leads. Because FBDD is still a relatively new drug discovery technology, further developments and optimizations in screening platforms and fragment exploitation can be expected. This review summarizes recent advances in FBDD platforms and discusses the factors important for the successful application of this technique.
Under the FBDD approach, both identifying the starting fragment hit to be developed and generating the drug lead from that starting fragment hit are important. Integration of various techniques, such as computational technology, X-ray crystallography, NMR, surface plasmon resonance, isothermal titration calorimetry, mass spectrometry and high-concentration screening, must be applied in a situation-appropriate manner.
片段药物发现（FBDD）已被确立为一种强大的替代和补充传统高通量筛选技术，用于识别药物先导物。目前，这种技术在学术团体以及小型生物技术公司和大型制药公司中都得到了广泛应用。近年来，已有超过 10 种采用 FBDD 开发的新化合物进入临床开发阶段，药物发现领域越来越关注这种技术。
在 FBDD 方法下，通过各种方法筛选相对较小化合物（分子量=100-300 Da）的片段文库，鉴定出的片段命中物通常与靶标弱结合，可作为产生更有效药物先导物的起点。由于 FBDD 仍然是一种相对较新的药物发现技术，因此可以预期在筛选平台和片段开发方面会有进一步的发展和优化。本综述总结了 FBDD 平台的最新进展，并讨论了成功应用该技术的重要因素。
在 FBDD 方法下，确定要开发的起始片段命中物和从该起始片段命中物生成药物先导物都很重要。必须以适当的方式整合各种技术，如计算技术、X 射线晶体学、NMR、表面等离子体共振、等温滴定量热法、质谱和高浓度筛选。
