Garner Philip, Cox Philip B, Rathnayake Upendra, Holloran Nicholas, Erdman Paul
Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, United States.
Discovery Chemistry and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064-6217, United States.
ACS Med Chem Lett. 2019 Apr 12;10(5):811-815. doi: 10.1021/acsmedchemlett.9b00070. eCollection 2019 May 9.
Fragment-based drug discovery (FBDD) is a well-established technology for lead compound generation in drug discovery. As this technology has evolved, the design of fragments for screening has also evolved to engender not just an understanding of the role of modulating the physicochemical properties of fragments (Rule of Three, Ro3) but also the importance and implications of incorporating shape and, in particular, 3D characteristics into fragments. Herein, we describe the design and synthesis of pyrrolidine-based fragments with good fragment-like (Ro3) physicochemical properties that effectively sample three-dimensional molecular space.
基于片段的药物发现（FBDD）是药物发现中用于生成先导化合物的一项成熟技术。随着这项技术的发展，用于筛选的片段设计也在不断演进，不仅要理解调节片段物理化学性质的作用（“类药五规则”，Ro3），还要认识到将形状，特别是三维特征纳入片段的重要性和意义。在此，我们描述了具有良好类片段（Ro3）物理化学性质的吡咯烷类片段的设计与合成，这些片段能够有效地对三维分子空间进行取样。
