Bauman Joseph D, Patel Disha, Arnold Eddy
Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
Top Curr Chem. 2012;317:181-200. doi: 10.1007/128_2011_232.
Fragment screening has proven to be a powerful alternative to traditional methods for drug discovery. Biophysical methods, such as X-ray crystallography, NMR spectroscopy, and surface plasmon resonance, are used to screen a diverse library of small molecule compounds. Although compounds identified via this approach have relatively weak affinity, they provide a good platform for lead development and are highly efficient binders with respect to their size. Fragment screening has been utilized for a wide range of targets, including HIV-1 proteins. Here, we review the fragment screening studies targeting HIV-1 proteins using X-ray crystallography or surface plasmon resonance. These studies have successfully detected binding of novel fragments to either previously established or new sites on HIV-1 protease and reverse transcriptase. In addition, fragment screening against HIV-1 reverse transcriptase has been used as a tool to better understand the complex nature of ligand binding to a flexible target.
片段筛选已被证明是药物发现传统方法的一种强大替代方法。生物物理方法，如X射线晶体学、核磁共振光谱和表面等离子体共振，被用于筛选各种小分子化合物库。尽管通过这种方法鉴定出的化合物亲和力相对较弱，但它们为先导物开发提供了一个良好的平台，并且就其大小而言是高效的结合剂。片段筛选已被用于广泛的靶点，包括HIV-1蛋白。在这里，我们综述了使用X射线晶体学或表面等离子体共振针对HIV-1蛋白的片段筛选研究。这些研究成功地检测到新型片段与HIV-1蛋白酶和逆转录酶上先前确定的或新的位点的结合。此外，针对HIV-1逆转录酶的片段筛选已被用作一种工具，以更好地理解配体与柔性靶点结合的复杂性质。
