Hit ID

Innovative hit-identification strategies

Dynamic combinatorial chemistry (DCC) has been applied to a wide range of fields as diverse as protein folding and materials science. Over the past decades, DCC has been applied to the identification of bioactive compounds as pioneered by Lehn. DCC enables the formation of a dynamic combinatorial library (DCL), in which the bonds linking the building blocks are formed reversibly. Upon addition of a specific target, one or more library member(s) bind(s), shifting the equilibrium and leading to selection and amplification of the strongest binders from the DCL. As a result, the medicinal chemist no longer needs to synthesise the adducts resulting from all possible combinations of building blocks but only those, which have been selected by the target, leading to a substantial decrease in synthetic effort. We have demonstrated for the first time that a combination of de novo SBDD or fragment linking in FBDD and DCC are highly efficient and synergistic strategies for hit identification or –optimisation, respectively. In this way, one can design in some flexibility and include building blocks that probe design hypotheses or target flexibility. This strategy is of particular importance for novel drug targets for which little structural information is available. 

Kinetic target-guided synthesis (KTGS) or protein-templated synthesis is a convenient strategy for hit identification. Only those products resulting from the most suitable combination of building blocks will be formed in the protein’s binding pocket. KTGS has found application to a range of protein targets, using only a few reactions to date, the most prominent being in situ click chemistry.  

To fulfil their promise and demonstrate that the use of DCC can accelerate drug discovery in its early stages, application to a wide range of promising or un(der)explored drug targets is needed. Besides this, we are establishing novel, unprecedented reactions for both DCC and KTGS to expand the currently available toolboxes. 

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Anna Hirsch

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