Eaton Hugh L, Wyss Daniel F
Global Structural Chemistry, Merck Research Laboratories, Kenilworth, New Jersey, USA.
Methods Enzymol. 2011;493:447-68. doi: 10.1016/B978-0-12-381274-2.00017-0.
Fragment-based drug discovery (FBDD) has become increasingly popular over the last decade as an alternate lead generation tool to HTS approaches. Several compounds have now progressed into the clinic which originated from a fragment-based approach, demonstrating the utility of this emerging field. While fragment hit identification has become much more routine and may involve different screening approaches, the efficient progression of fragment hits into quality lead series may still present a major bottleneck for the broadly successful application of FBDD. In our laboratory, we have extensive experience in fragment-based NMR screening (SbN) and the subsequent iterative progression of fragment hits using structure-assisted chemistry. To maximize impact, we have applied this approach strategically to early- and high-priority targets, and those struggling for leads. Its application has yielded a clinical candidate for BACE1 and lead series in about one third of the SbN/FBDD projects. In this chapter, we will give an overview of our strategy and focus our discussion on NMR-based FBDD approaches.
在过去十年中，基于片段的药物发现（FBDD）作为一种替代高通量筛选（HTS）方法的先导化合物生成工具，越来越受到欢迎。目前已有几种源自基于片段方法的化合物进入临床试验阶段，证明了这一新兴领域的实用性。虽然片段命中物的识别已变得更加常规，可能涉及不同的筛选方法，但将片段命中物有效推进到高质量的先导化合物系列中，仍然可能是FBDD广泛成功应用的一个主要瓶颈。在我们实验室，我们在基于片段的核磁共振筛选（SbN）以及随后使用结构辅助化学对片段命中物进行迭代推进方面拥有丰富经验。为了最大化影响力，我们已将这种方法战略性地应用于早期和高优先级靶点，以及那些难以获得先导化合物的靶点。其应用已为三分之一左右的SbN/FBDD项目产生了一种用于β-分泌酶1（BACE1）的临床候选药物和先导化合物系列。在本章中，我们将概述我们的策略，并重点讨论基于核磁共振的FBDD方法。
