As mentioned last week, advancing fragments in the absence of structure is a major challenge. But how much of a barrier is it really?
I know some researchers who would not consider moving forward with a fragment in the absence of a crystal structure. As crystallography continues to advance, more targets will be available, but many will remain out of reach for the foreseeable future.
Of course, the first SAR by NMR paper used NMR rather than crystallography, and the early work that ultimately led to venetoclax relied only on NMR-derived structures. Similarly, crystallography was initially unsuccessful against MCL-1, but NMR-based models allowed effective fragment advancement.
When crystallography and NMR both fail, there is in silico modeling, which continues to improve. Last year we highlighted how modeling succeeded in merging fragments to a nanomolar binder.
But the real challenge is advancing fragments with no structural information whatsoever. There are a few published examples (such as this and this). And it’s worth remembering that optimization in the absence of structure was how drug discovery was done decades ago, before the rise of biophysics. Indeed, until recently most GPCR-based drug discovery was done without the benefit of structural information.