Desjarlais Renee L
Structural Biology, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Spring House, Pennsylvania, USA.
Methods Enzymol. 2011;493:137-55. doi: 10.1016/B978-0-12-381274-2.00006-6.
Fragment-based drug discovery has emerged over the past 15 years as an effective lead discovery paradigm that is complementary to traditional high-throughput screening. The starting point for fragment-based drug discovery is the identification of low-molecular weight, typically low-affinity compounds that bind to a target of interest. These fragments can then be elaborated by growing or linking to create compounds with high affinity and selectivity. A wide variety of techniques from the computational chemistry tool chest can be applied in a fragment-based project. The computational tools are equally useful in combination with experimental-binding determination or in a completely in silico design procedure. This chapter will outline these techniques, their utility, and their validation in the design of novel lead compounds.
在过去15年里，基于片段的药物发现已成为一种有效的先导化合物发现模式，它是对传统高通量筛选的补充。基于片段的药物发现的起点是识别与感兴趣的靶点结合的低分子量、通常是低亲和力的化合物。然后可以通过扩展或连接这些片段来构建具有高亲和力和选择性的化合物。计算化学工具库中的各种技术都可应用于基于片段的项目中。这些计算工具在与实验性结合测定相结合时，或在完全基于计算机的设计过程中同样有用。本章将概述这些技术、它们的用途以及它们在新型先导化合物设计中的验证。
