Fragment-based drug discovery (FBDD) has become a mainstream technology for the identification of chemical hit matter in drug discovery programs. To date, the food and drug administration has approved four drugs, and over forty compounds are in clinical studies that can trace their origins to a fragment-based screen. The challenges associated with implementing an FBDD approach are many and diverse, ranging from the library design to developing methods for identifying weak affinity compounds. In this article, we give an overview of current progress in fragment library design, fragment to lead optimisation and on the advancement in techniques used for screening. Finally, we will comment on the future opportunities and challenges in this field.
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Cover Image
Cover Image
The cover image depicts a combination of a 3D reconstruction of ER-TGN contact sites by focus ion beam-scanning electron microscopy (FIB-SEM) and five images showing the visualization of the contacts by FRET/FLIM. The 3D reconstruction of the Golgi stack was generated from FIB-SEM tomography of a HepG2 cell using IMOD software. The ER cisterna is shown in red (with ribosomes as white circles), while the trans-most cisterna of the Golgi stack is shown in green (with emerging clathrin-coated buds decorated by pink dots). The five FLIM images are from HeLa cells expressing a TGN reporter (TGN46-GFP) and an ER reporter (mCherry-Cb5). The pseudocolour scale represents donor (i.e. GFP) lifetime (τ) values ranging from 1.8 (blue) to 2.7 ns (red) under conditions that destabilize (left) or stabilize ER-TGN contact sites. For further information, see the review by Venditti and colleagues (pp. 187–197). Image courtesy of Maria Antonietta De Matteis.
Fragments: where are we now?
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