08 May 2017

Poll: structural information needed for fragment optimization

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.

So, in the poll to the right please choose the minimum level of structural information you would need to embark on a fragment to lead program. Happy voting!

1 comment:

Robert Soliva said...

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)