Fragment-based approaches are often applied to tough targets, such as protein-protein interactions or BACE1, that have stymied more conventional approaches. Although kinases have certainly been the focus of many fragment efforts, other more “traditional” enzymes are sometimes ignored. In a recent paper in J. Med. Chem., Takeshi Hondo, Tatsuya Niimi, and colleagues at Astellas Pharma show that fragments can play a valuable role here too.
The researchers were interested in D-amino acid oxidase (DAAO), a potential schizophrenia target. This enzyme catalyzes the deamination of amino acids such as D-serine, so it is not surprising that very small, fragment-sized molecules can bind to it quite tightly (as indeed we noted here). Recognizing this, the researchers conducted a high-concentration screen of 3500 fragments. One of the more interesting hits was compound 8, which is actually a fragment of a previously reported molecule. With low micromolar potency and just 8 atoms, the fragment has a ligand efficiency of just over 1 kcal mol-1 atom-1, one of the highest values I’ve ever seen.
In addition to its impressive affinity and ligand efficiency, compound 8 induced a conformational change in the protein to open a nearby subpocket, and growing into this pocket led to dramatic improvements in potency. Additional optimization for permeability and brain penetration eventually led to compound 30, with low nanomolar activity in both biochemical and cell-based assays. This compound proved to be selective against a panel of 57 potential off-targets, and was found to be active when dosed orally in a mouse model of schizophrenia.
This is a lovely example of structure-based fragment growing. Although it’s rare to find such a small, potent fragment, examples such as this do support the inclusion of very small fragments in screening libraries.