Fragment Based Drug Discovery
Traditional high-throughput screening has not delivered on its promise of increasing the numbers and quality of new drugs entering clinical trials.
This lack of success is due in part to the complexity and the relatively large size of the compounds routinely being screened. This problem can be addressed by fragment-based drug discovery, an alternative approach, which uses as starting points very small, low molecular weight, drug fragments. These fragments have the potential to keep the overall complexity and molecular weight of each drug candidate low, a key factor in successful drug development.
Traditional bioassays used in high-throughput screening are generally unable to detect such small drug fragments because of their low potency binding to the protein target.
Astex’s Pyramid™ platform integrates biophysical techniques such as X-ray crystallography, nuclear magnetic resonance spectroscopy and isothermal calorimetry with fragment library design and a range of computational methodologies into a proprietary approach for fragment-based drug discovery. Due to the very high sensitivity of Pyramid™, unique ligands, not generally detectable using conventional screening techniques, can be routinely identified. A key aspect of Pyramid™ is that it affords a detailed understanding of the ligand’s binding environment at an atomic level and such structural insights support a very efficient hits-to-leads optimisation process. Each atom is designed to contribute to protein binding in a defined and productive manner. This high “ligand efficiency” results in drug candidates having lower molecular weight, reduced metabolic liability, improved target selectivity and ease of chemical synthesis.