Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections

Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small “fragment” molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds. Diversity-oriented synthesis (DOS) is a synthetic strategy that aims to efficiently produce compound collections with high levels of structural diversity and three-dimensionality and is therefore well-suited for the construction of novel fragment collections. This Mini-Review highlights recent studies at the intersection of DOS and FBDD aiming to produce novel libraries of diverse, polycyclic, fragment-like compounds, and their application in fragment-based screening projects.