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.
Posts
1 comment:
X-ray and NMR are definitely key. We would not say otherwise. But it is true that computational methods are becoming more and more reliable thanks to the optimization of algorithms and ever-increasing compute power.
We wanted to test our MonteCarlo technology, PELE, for binding mode (pose) prediction of very small to medium sized fragments in an extremely challenging case, soluble Epoxide Hydrolase, which has a very big, highly hydrophobic and flexible active site, able to accomodate a wide range of chemical cores and whose adaptability offers a wild range of pharmacophores. We could determine the right binding mode for all fragments which would have been effectively used to guide medicinal chemistry efforts. We even found the multiple binding modes for very small fragments that could bind simulteneously in two different pockets of the huge binding site. We contributed this study in the BMC issue celebrating Bill Jorgensen's birthday (https://www.ncbi.nlm.nih.gov/pubmed/27545443)
Post a Comment