Hoffer Laurent, Renaud Jean-Paul, Horvath Dragos
Laboratoire d'Infochimie, CNRS UMR7177, Université de Strasbourg, 4 rue Blaise Pascal, 67000 Strasbourg, France.
Comb Chem High Throughput Screen. 2011 Jul;14(6):500-20. doi: 10.2174/138620711795767884.
Fragment-based screening is an emerging technology which is used as an alternative to high-throughput screening (HTS), and often in parallel. Fragment screening focuses on very small compounds. Because of their small size and simplicity, fragments exhibit a low to medium binding affinity (mM to µM) and must therefore be screened at high concentration in order to detect binding events. Since some issues are associated with high-concentration screening in biochemical assays, biophysical methods are generally employed in fragment screening campaigns. Moreover, these techniques are very sensitive and some of them can give precise information about the binding mode of fragments, which facilitates the mandatory hit-to-lead optimization. One of the main advantages of fragment-based screening is that fragment hits generally exhibit a strong binding with respect to their size, and their subsequent optimization should lead to compounds with better pharmacokinetic properties compared to molecules evolved from HTS hits. In other words, fragments are interesting starting points for drug discovery projects. Besides, the chemical space of low-complexity compounds is very limited in comparison to that of drug-like molecules, and thus easier to explore with a screening library of limited size. Furthermore, the "combinatorial explosion" effect ensures that the resulting combinations of interlinked binding fragments may cover a significant part of "drug-like" chemical space. In parallel to experimental screening, virtual screening techniques, dedicated to fragments or wider compounds, are gaining momentum in order to further reduce the number of compounds to test. This article is a review of the latest news in both experimental and in silico virtual screening in the fragment-based discovery field. Given the specificity of this journal, special attention will be given to fragment library design.
基于片段的筛选是一种新兴技术，它被用作高通量筛选（HTS）的替代方法，并且常常与之并行使用。片段筛选聚焦于非常小的化合物。由于其尺寸小且结构简单，片段表现出低至中等的结合亲和力（毫摩尔至微摩尔），因此必须在高浓度下进行筛选以检测结合事件。由于在生化分析中高浓度筛选存在一些问题，所以在片段筛选活动中通常采用生物物理方法。此外，这些技术非常灵敏，其中一些能够提供有关片段结合模式的精确信息，这有助于进行必要的从命中化合物到先导化合物的优化。基于片段筛选的主要优势之一在于，相对于其尺寸而言，片段命中化合物通常表现出较强的结合能力，并且与从高通量筛选命中化合物衍生出的分子相比，对其进行后续优化有望得到具有更好药代动力学性质的化合物。换句话说，片段是药物发现项目中很有吸引力的起始点。此外，与类药物分子相比，低复杂度化合物的化学空间非常有限，因此使用规模有限的筛选文库更容易进行探索。而且，“组合爆炸”效应确保相互连接的结合片段所产生的组合可能覆盖“类药物”化学空间的很大一部分。与实验筛选并行的是，专门针对片段或更广泛化合物的虚拟筛选技术正日益受到关注，以便进一步减少待测试化合物的数量。本文综述了基于片段发现领域中实验性筛选和计算机虚拟筛选的最新进展。鉴于本期刊的特殊性，将特别关注片段文库的设计。
