Route to three-dimensional fragments using diversity-oriented synthesis
Route to three-dimensional fragments using diversity-oriented synthesis
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DOI：
10.1073/pnas.1015271108
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发表时间：
2011-04-26
影响因子：
11.1
通讯作者：
Young, Damian W.
中科院分区：
文献类型：
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作者：
Hung, Alvin W.;Ramek, Alex;Young, Damian W.
基于片段的药物发现(FBDD)已被证明是一种生产高质量化学配体的有效手段，作为药物发现追求的起点。使用FBDD方法开发的临床候选药物的数量不断增加，这证明了这种方法的有效性。基于片段的方法的成功高度依赖于用于筛选的片段文库的同一性。FBDD的绝大多数都集中在富含sp2的芳香化合物的使用上。具有更多3D特征的扩展碎片集将提供比目前使用的碎片更大的化学空间。面向多样性的合成(DOS)旨在高效地合成一组具有不同骨架和立体化学性质的分子。从DOS衍生的分子在调节各种“困难”靶标的功能方面也表现出显著的成功。在这里，我们描述了DOS在构建一组独特的片段方面的应用，该片段集包含高度富含SP3的骨架，用于基于片段的筛选。利用化学信息学分析，我们量化了新的3D碎片的形状和物理性质，并将它们与包含已知碎片样分子的数据库进行了比较。
Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp2-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various "difficult" targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp3-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.