Begley Darren W, Davies Douglas R, Hartley Robert C, Edwards Thomas E, Staker Bart L, Van Voorhis Wesley C, Myler Peter J, Stewart Lance J
Emerald BioStructures, Bainbridge Island, Washington, USA.
Methods Enzymol. 2011;493:533-56. doi: 10.1016/B978-0-12-381274-2.00021-2.
Structural genomics efforts have traditionally focused on generating single protein structures of unique and diverse targets. However, a lone structure for a given target is often insufficient to firmly assign function or to drive drug discovery. As part of the Seattle Structural Genomics Center for Infectious Disease (SSGCID), we seek to expand the focus of structural genomics by elucidating ensembles of structures that examine small molecule-protein interactions for selected infectious disease targets. In this chapter, we discuss two applications for small molecule libraries in structural genomics: unbiased fragment screening, to provide inspiration for lead development, and targeted, knowledge-based screening, to confirm or correct the functional annotation of a given gene product. This shift in emphasis results in a structural genomics effort that is more engaged with the infectious disease research community, and one that produces structures of greater utility to researchers interested in both protein function and inhibitor development. We also describe specific methods for conducting high-throughput fragment screening in a structural genomics context by X-ray crystallography.
传统上，结构基因组学的工作重点是生成独特且多样的靶标的单个蛋白质结构。然而，给定靶标的单一结构往往不足以确定其功能或推动药物研发。作为西雅图传染病结构基因组学中心（SSGCID）的一部分，我们试图通过阐明针对选定传染病靶标的小分子 - 蛋白质相互作用的结构集合来扩展结构基因组学的重点。在本章中，我们讨论小分子文库在结构基因组学中的两种应用：无偏向性片段筛选，为先导化合物开发提供灵感；以及基于知识的靶向筛选，以确认或校正给定基因产物的功能注释。这种重点的转变使得结构基因组学的工作更紧密地与传染病研究界合作，并且能够产生对蛋白质功能和抑制剂开发感兴趣的研究人员更有用的结构。我们还描述了在结构基因组学背景下通过X射线晶体学进行高通量片段筛选的具体方法。
