Research Case Studies

Applications of structure- and fragment-based drug discovery

Fragment-based discovery identifies low molecular weight molecules which make key interactions with their target binding site. Fragments provide a range of efficient starting points from which potent ligands, and eventually drugs, can be developed. We have developed our proprietary library of fragments which has been successfully applied to more than 70 targets. Our library is typically screened using NMR spectroscopy with extensive orthogonal validation to provide robust series and the structure of bound fragments determined by X-ray crystallography.



We have pioneered the use of off-rate screening (ORS) to kinetically sample hit-to-lead chemical space, combining our expertise in cheminformatics, compound library synthesis and use of surface plasmon resonance (SPR), to enable screening of unpurified reaction products. This has been applied to the rapid generation of lead compounds from fragment hits without purification of compound libraries or protein structure.

Key to many of our projects is target enablement – devising innovative methods to solve problems in exploratory research to establish a robust platform for drug discovery on a target.  We then combine structural, thermodynamic and kinetic information to design novel potent drug-like molecules. Examples include generation of lead compounds that inhibit protein-protein interactions, ATPases and kinases, leading to pre-clinical candidates for Mcl-1, Bcl-2, Hsp90 and Chk1. There are also published examples of how our approach identified novel zinc-chelating lead compounds for LpxC, using our expertise in protein engineering, expression and crystallography to generate Chk1-derived surrogates of LRRK2 and use of our ORS technology in the identification of novel inhibitors of PDHK.