Structure-based drug design of small-molecule inhibitors facilitated by dynamic combinatorial chemistry


Drug discovery is a challenging undertaking. In a context where the pharmaceutical industry finds it increasingly difficult to develop new drugs, efficient access to novel molecular scaffolds is urgently needed.
In this project, I will develop novel inhibitors for challenging and important drug targets, in particular, an anti-infective and an anticancer target using unprecedented combinations of computational and experimental techniques aimed at accelerating the drug-discovery process: dynamic combinatorial chemistry (DCC) in combination with fragment-based drug design, (de novo) structure-based drug design (SBDD) and multi-component reactions. By doing so, hitherto untouched regions of the chemical space become accessible as well as novel interaction modes. At the same time, the full potential, generality and wider applicability of biomedical DCC will be demonstrated by taking it into the arena of challenging drug-discovery projects.
To date, biomedical DCC has focussed primarily on the underlying chemistry. I will establish protocols enabling the use of sub-stoichiometric amounts of protein and larger libraries, two important bottlenecks of DCC that need to be overcome to be in a position where DCC can be applied to real drug targets, also by the pharmaceutical industry. To enable direct validation of the binding mode of the binders, I will establish protein crystallography as an analytical tool for DCC.
This VIDI project will accelerate the identification of novel bio-active compounds by pushing the frontier of biomedical DCC, which is an outstanding tool to accelerate the drug-discovery process given that it gives access to large numbers of compounds without requiring individual synthesis and purification of all library members. My expertise in synthetic organic chemistry, DCC, SBDD and medicinal chemistry position me for achieving the ambitious goals set out in the proposal and my established collaborations with protein crystallographers and biochemists will ensure rapid utilisation and uptake of the results.





Prof. dr. A.K.H. Hirsch

Verbonden aan

Rijksuniversiteit Groningen, Faculty of Science and Engineering (FSE), Stratingh Instituut voor Chemie


Mr. AM Hartman MSc, Prof. dr. A.K.H. Hirsch, Dr. V.R. Jumde, Dr. M Mondal, N.B. Niet Bekend en Niet Gebruiken, Mr. R van der Vlag MSc


16/09/2015 tot 13/11/2019