Fragment-based drug discovery is gaining momentum as an efficient strategy to find and optimize leads. The technology first identifies small chemical fragments that bind weakly, yet efficiently, to the target, and then grows or combines them to produce a lead with a higher affinity.
Fragment-based discovery differs from high-throughput screening. The latter assesses libraries with up to millions of compounds bearing molecular weights of around 500 daltons and nanomolar binding affinities. In contrast, the early phase fragment-based lead discovery screens libraries with a few thousand compounds with molecular weights of ~200. The hits that have comparably low binding affinities are then optimized.
At the recent CHI conference on fragment-based drug discovery, participants discussed challenges and new insights into this emerging technology.
“To understand the concept of fragment-based drug design, think of a drug molecule as composed of building blocks like Legos™,” recommended Eric Springman, Ph.D., head of discovery, Locus Pharmaceuticals. “Pieces are connected to build up the compound. This is in antithesis to high-throughput screening, where large libraries of elaborate compounds are scoured to find a starting point for drug discovery.
“There are important advantages to fragment-based design. First, because you start with something that is less complex, you can effectively screen a broader swath of chemical space and make the final product more efficient. Second, experience from combinatorial chemistry and high-throughput screening has taught us to emphasize certain drug characteristics early in the discovery process. In fragment based-design, you can choose these characteristics from the very beginning of the process.”