Fragment-based drug discovery is a powerful tool for the discovery of new drugs. The approach relies on screening of smaller molecules (so-called fragments), which affords a series of advantages over the traditional high-throughput screening. Due to the smaller size of these fragments, the chance of binding to a protein target is significantly increased. This greatly speeds up the process of finding new hit compounds to use as starting points for the development of future drugs. However, in spite of the success of fragment-based drug discovery, the approach still suffers from a limited diversity of fragments applied and laborious screening workflows.
In an effort to address these challenges, two novel fragment libraries for use in fragment-based drug discovery were constructed. In the first library, a collection of 115 fluorine-containing fragments were synthesized to enable elegant screening by 19F NMR spectroscopy. To demonstrate the usefulness of this library, biological evaluation using 19F NMR spectroscopy was performed against a number of disease-related targets. This resulted in the identification of multiple new and promising hit compounds.
In the second library, 42 diverse fragments inspired by natural products were synthesized from two similar building blocks. The fragments exhibited desirable properties including a high degree of shape diversity and incorporation of multiple exit vectors for easier development into potential drug candidates.