Protein-Protein Interaction Inhibitor Design
NQuiX has developed novel technology for the design of protein-protein interaction inhibitors (PPIi). This is based on the method of Garland and Dean in which drug-like non-peptide small molecules are selected such that they can place correctly the key amino acid side-chains of a given recognition segment. Originally developed for β-turn mimetics, the method can now be applied generally to any known or putative bioactive conformation. Enhanced scoring is applied in the selection of templates with additional favourable characteristics and further developments allow alternative solutions as well as more compact arrangements, where appropriate.
The methods have been applied in the design of focused screening libraries for regular secondary structure conformations, notably the α-helix, and targeting specific bioactive conformations for individual protein-protein interaction targets. Screening collections can also be profiled for their ability – or not – to mimic a desired recognition motif. This style of analysis provides focused sets for screening and often rationalises the relative failure of diversity screening approaches, whilst simultaneously demonstrating the need for targeted synthesis of specific compounds.
For the original publications in the area, see:
- Garland, S. L.; Dean, P. M. Design criteria for molecular mimics of fragments of the β-turn. 1. Cα atom analysis. J. Comput. Aided. Mol. Des. 1999, 13, 469–483.
- Garland, S. L.; Dean, P. M. Design criteria for molecular mimics of fragments of the β-turn. 2. Cα–Cβ bond vector analysis. J. Comput. Aided. Mol. Des. 1999, 13, 485–498.