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.”
Locus conducts contract drug discovery research and also has internal discovery programs targeting protein kinases in cancer and inflammation.
“We use our computational platform to model proteins and to simulate fragment binding,” added Dr. Springman. “This requires a solid core of high performance computing to handle and mine the vast data sets we generate. One cornerstone of our platform is based on patented methods for estimating the free energy of binding for virtual drug fragments that are selected from an in-house database of ~15,000.
“The power of virtual fragment simulations is in the combinatorial search of chemical space. For instance, if we are looking for a molecule composed of three fragments and we simulate 2,000–5,000 fragments, we’re searching chemical space equivalent to 8–125 billion possible combinations. That’s 1,000-fold larger than a typical chemical library."
Dr. Springman provided a perspective on this new and emerging field. “Fragment-based approaches have led to a paradigm shift in the field of drug discovery. The fragment-based approach has enabled a much more close and productive relationship between computational chemists and medicinal chemists.
“In the past, there has often been a large gulf between the two, with each having different perspectives on the process of drug design. Fragment-based methods click with the way medicinal chemists think and the process is necessarily prospective in nature. This brings the two sides together to decide what to focus on and how to construct it. Ultimately, it is leading to an improved way to produce drugs.”