About

During recent years drug discovery has emerged into a fully integrated scientific discipline. More and more of the very early steps in the ultimately difficult and costly process to get a new drug to the market are now integrated into academic labs. Within the growing academic community in the area of chemical biology and early phase drug discovery, our lab focuses on the development and application of alternative integrated process to identify new small molecule, peptidomimetic and biosimilar ligands for the most challenging target proteins. Within the so called families of “undruggable” targets, protein-protein interactions, enzymatic targets in the field of the ubiquitin proteasome system, and intrinsically unfolded proteins are within the top ranked class of proteins with which big Pharma is struggling. Using alternative, and pragmatic approaches we develop methods to suggest, produce, find and evaluate chemical and biological entities. In combining basic quantitative molecular recognition science with initial drug discovery efforts, we identify small molecular tool compounds and biosimilar probes which can be further developed from hits to lead compounds and applied to chemically validate protein targets. The three disease areas CTB focuses their efforts on are cancer, infectious diseases and neurodegenerative diseases (particularly Parkinson’s). Supported by developments from our efforts in the core areas of biology, chemistry and engineering, CTB has developed four screening platforms which are integrated into one discovery process.

(1) The Chemoinformatics and in-silico screening platform (LBSSX) helps us to define which compounds or libraries should be prioritized for testing. LBSSX is further applied for industrial library annotation, target identification, ligand and library based similarity analysis and for the design of novel drug combinations. MorPH, shown in figure 1 is an additional software package for the iterative semi-automated development of peptidomimetics.

1a. Molecular similarity platform, 1b. Protein promiscuity map, 1c. Cone-angle restrictive docking, 1d. Morphing of peptides into stable peptidomimetics, scheme and morphed Shugoshin peptidomimetic bound to Survivin

(2) The Label Free Affinity screening Platform (LFAP); exemplary techniques shown in figure 2, is used to identify compounds which bind to a target, measure their affinities, identify aggregating compounds, and even goes as far as determining whether a small molecule binds to the target specifically in cell lysates and cells. Diverse biophysical techniques include pbSEC, fC, qµD, magB, TAPS, TDA, HDX, FBS & F-NMR which cover ranges of 10 mM to picomolar affinities of binders to be found.