WP4

Library design and compound selection (virtual screening, scaffold selection, library design)
The aim is to design compounds to interfere with TS dimerization by binding to the TS monomer-monomer interface.

The design strategy will be two-pronged:

1. Design of peptides and peptidomimetics based on knowledge that peptides from the sequence of TS can affect dimerization and bind to the TS monomer. These peptides will be further optimized for binding to the TS monomer and libraries of peptidomimetics will be designed.

2. Fragment based de novo ligand design to identify low-affinity ligand/fragments by cysteine tethering and to optimize these to obtain high-affinity ligands.

To aid the ligand design, modelling and simulation will also be performed, for the interaction of TS with its mRNA and the effect of small ligands on this interaction. All ligand design, will be accompanied by in silico ADME screening (see WP4).
All design studies will target the human TS, and involve comparison with the homologous TSs from microorganisms.

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