Fragment-Based Lead Generation
Traditional methods of drug optimization often rely heavily on derivitization of a single chemical scaffold. Drug discovery programs can be stalled if it is discovered that the chosen scaffold has inherent liabilities that limit its use in potential drugs. Generation of diverse chemical scaffolds as starting points for optimization greatly increases the chances of discovering inhibitors with drug-like properties. To generate diverse chemical scaffolds, Trius uses a fragment-based SBDD strategy. In our approach, we develop a pharmacophore model based on the most highly conserved regions of the active-site pocket of the protein target. Based on this pharmacophore model, we use computational methods to select small, focused libraries of low molecular weight compounds and screen them using x-ray crystallographic methods to identify fragments that bind to the target. The advantage of using crystallography as a screening tool is that we can characterize the binding of small molecular weight fragments that would not be detected using conventional assay methods. Determination of the structures of these fragments bound to the target provides starting points for generating diverse lead series where additional fragments are connected to increase potency by new interactions with the enzyme. In this process, we give prioritization to design concepts that yield compounds with good drug properties.