Sometimes, in the FBHG arena, we get deep into the weeds. I am a simple man, with a simple understanding of FBHG. There are a few tenets that I hold dear: Small, not very complex molecules have less of a chance of bad interactions. You need high sensitivity (read:biophysical) methods to detect them robustly. Libraries don't need to be bigger than a few thousand. Now, this last one can be/has been/will be a subject of much debate. There is no way to cover ALL of available chemical space and still run a screen in this lifetime. However, I think most people agree that you can sample an "adequate" (that term being highly fungible) amount of available chemical space with a few thousand compounds. Heck, if you have the resources to screen 10,000s of fragments, go right ahead.
But, what molecules should be in your fragment collection? To paraphrase Justice Brandeis, you know a good fragment when you see it. I think every body could have the same 2000 or so fragments and each find their own success. However, we are lucky that there are a metric boatload of commercial vendors of fragments, so we won't have to. In this paper, the authors aim to determine what is currently available in commercial fragment space (emolecules) that covers known medchem space. They use CHEMBL as the source of "medchem" space and analyzed the distribution of biologically active molecules and discovered property trends that differentiate active from inactive. Here are there results:
In their discussion, they state:
While many typical fragment libraries contain commercial fragments that mostly conform to the Ro3 physicochemical properties criteria, the chemical space these fragments represents may not entirely project to the leadlike and drug-like chemical space that are relevant to medicinal chemistry.
They realize that the overlap between fragment space and CHEMBL-medchem space do not overlap well. In fact, almost half of the bioactive-derived substructures are not covered by commercially available fragments. They propose that fragment libraries should focus on those structures represented by bioactive CHEMBL compounds. They make some suggestions to expand fragment libraries, e.g. polar fragments that are not similar to commercial fragments and more 3D-arity. However, there is a paucity of these molecules commercially available, so they suggest synthetic focus should be placed here.
[Ed: Link to paper fixed. Sorry about that.]
[Ed: Link to paper fixed. Sorry about that.]
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8 comments:
link to paper incorrect
Is this from the 3D consortium another group?
I like the fact that they emphasize the need for more polar fragments; with all the talk about three-dimensional fragments, it is sometimes easy to forget that hydrophilic ones are also often under-represented.
But Dan, if polar fragment were easy to get/make wouldn't they already be commercially available? I would like cows to excrete beer, doesn't mean it is any more likely to happen.
I wonder if part of the reason is that ChEMBL does not capture the results from many of the assay types used to identify fragment hits (e.g. thermal shift etc).
I wonder what proportion of the pharmacophores in the overlapping region are artefacts?
The authors do apply filters to remove unwanted chemotypes, but I don't think that anyone really has a handle on structures that may appear bio-active but actually cause aggregation, are fluorescent artefacts etc.
Fosfomycin and fosmidomycin: polar compounds which are both fragments and antibiotic drug molecules. I think if anyone is going to pursue antimicrobials by fragments, having some small, polar, aliphatic material is key. How easy it is to make/obtain these materials, hard to say
We have not found it easy to obtain a wide array of small, polar, aliphatic fragments from the usual commercial vendors.
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