"Fragment based drug design (FBDD) has become a standard methodology in the drug industry. This paradigm dates back to 1996 with publication of the landmark paper in Science. The paradigm depends on screening of small, generally 250 to 300 Da, compounds termed fragments, which record weak affinities often in the millimolar range. These inhibitors can then be grown or linked up to form tight binding inhibitors. FBDD samples more chemical space than larger molecules, so smaller chemical libraries can be used. While the methodology has been notably successful, the use of linking strategies has lagged behind.

This review by Elizabeth Bedwell, William McCarthy, Anthony Coyne, and (the late) Chris Abell, a leading scientist in this field, looks at linker structure and how it relates to the properties of the final ligand. Dynamic combinatorial chemistry and kinetic target- guided synthesis, are highlighted as methods to watch. Linker design is a similarly difficult area for proteolysis targeted chimeras (PROTACs), and maybe there are some useful tips in this analysis."
- David Selwood

1. Discovering high-affinity ligands for proteins: SAR by NMR. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Science. 1996. 274(5292):1531-4.

1. Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors. Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray CW, Seavers LC, van Montfort RL. J Med Chem. 2006 Feb 23;49(4):1346-55.

Linker design for Fragment Based Drug Design

Free to Read for a limited time!