Fragment library design_Layout 1

Hit Generation (FBHG) overcomes many of the potential issues and inaccuracies encountered with the traditional approach of high throughput screening (HTS). For example, traditional screening libraries are commonly populated with molecules designed to adhere to Lipinski’s rule of five; however, they tend to be large and lipophilic, making them difficult to develop into potent compounds without compromising their ADME properties. Fragment libraries, on the other hand, can be filtered against a number of physiochemical properties, for instance to remove reactive groups and assure solubility. FBHG burst on the scene in 1996 when Abbott introduced the use of nuclear magnetic resonance (NMR) to guide structure-activity relationships (SAR) between compound and target. This approach, termed ‘SAR by NMR’1 coalesced the ideas of many existing concepts into an easily understandable process. Thus, FBHG started as an inherently NMR-based technique, and while crystallography played a significant role in early FBHG, NMR has traditionally remained the gold standard. In 2001, Chris Lepre laid out the key concepts for assembling a fragment library for NMR, which became the prevailing thought for fragment libraries2. He explained that they should include a large number of diverse compounds with high aqueous solubility, and be synthetically tractable for building into compounds.