Knowledge of the three-dimensional (3D) structure of protein targets is important for understanding their physical and functional properties. In particular, the detailed knowledge of intermolecular interactions with specific ligands revealed by the structure determination of complexes is essential for rationalizing affinity and specificity, key issues in the drug discovery and lead optimization process. Biostructural research at Polyphor, which takes advantage of the internally available cocrystallization & X-ray infrastructure and of the access to the Swiss Light Source (SLS), Villigen, Switzerland, supports the lead identification and lead optimization process both for our internal and collaborative projects.
Molecular design - Cheminformatics
Successful target focused drug design and development starts with an extensive collection and analysis of chemical and biological information leading to a so called “structure-activity-relationship” (SAR).
Understanding the impact of structural changes in our PEM and MacroFinder® molecules on their biological activity is essential for a directed optimization process.
Various algorithms are applied to identify molecular properties and fingerprint patterns to extract key features of active molecules on a chemical structure level. This knowledge supports the optimization of both biological activity and ADMET (adsorption, distribution, metabolism, excretion and toxicity) properties of our lead molecules until ultimately clinical drug candidates are identified.
Polyphor uses both commercially available and proprietary computational methods and tools to transfer SAR knowledge into valuable two-dimensional (2D) protein-/peptide-sequence and 3D structural information.
Docking and 3D pharmacophore searches or combinations of both methods are applied to understand biological activity and structure on a 3D level. Due to the modular nature of both technology platforms, virtual screening techniques can be efficiently applied to explore virtual 3D PEM and MacroFinder® prototype libraries to derive new design ideas or explore possible modifications based on experimental and structural findings.
In addition, molecular design is guided by the determination of the 3D structure of PEM or MacroFinder® molecules in solution by NMR or co-crystallized with proteins by X-ray crystallography.