Structure-Based Drug Design
The three-dimensional structure of a target protein, especially with bound ligand, is a valuable source of information to guide drug discovery. A number of structure-based tools, complemented by ligand-based approaches, can be used for the design and optimization of new compounds.
- Sygnature’s close collaboration with Peak Proteins allows us to generate protein constructs and obtain X-ray crystallography data on behalf of customers for targets lacking structural information and to elucidate the binding mode of representative leads to drive structure-based optimisation.
- We have extensive experience in generating homology models based on related proteins for any targets that lack structural data and prove difficult to crystallize.
- Our expert computational team analyses all available structural information and shares results and 3D visualization tools with the medicinal chemistry teams to encourage idea generation and improve compound design.
- Flexible ligand docking and 4D docking, to account for protein flexibility, are applied to prioritize design ideas and a 3D fully-interactive ligand editor can be used for ligand optimization in the binding site.
- We can apply water assessment technology to identify favourable and unfavourable regions of solvent thermodynamics in the binding site. Introduction of polar functionalities to a lead compound, based on this understanding of the water structure, can often benefit physical properties as well as potency and specificity.
We are passionate about acquiring and using cutting-edge tools to advance drug discovery and are always looking for ways to improve our capabilities. For example, we are currently working on the implementation of Free Energy Perturbation (FEP) calculations to obtain an accurate prediction of protein-ligand binding free energies.