A friend recently asked if I knew of any commercial fragment collections. She knows someone in academia who is interested in exploring fragment-based ligand discovery, and would like to get started with a well-curated library.
At Sunesis, we used custom-built, disulfide-containing fragments for Tethering, but of course most techniques aren't limited to disulfides.
So everyone, does your company sell fragments? Now is your chance to get some free advertising!
Or have you purchased fragment libraries? Did you like them? If not, now is your chance to get some free complaining!
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4 comments:
I’ve been involved in selection of compounds for generic (with respect to assay technology and target) fragment screening and NMR screening. We’re always on the lookout for interesting fragments and have, on occasion, even had compounds specially synthesized. We’re typically more interested in acquiring individual compounds than complete libraries. This is because we often already have substantial stocks of some compounds in the commercial library and because of perceived design deficiencies (e.g. lack of diversity of molecular recognition elements that can be presented to targets). Sample availability is an important issue when we acquire fragments for generic screening because we typically make up 1-2ml of 100mM stock solutions.
Using a commercial fragment library would make more sense for an academic lab or small start up with limited compound management infrastructure. Companies aiming to meet this market need would be well advised to share the principles according to which their libraries have been designed since it is relatively easy to package some low molecular weight compounds (e.g. reagents) as a fragment library. Attempting to market ‘unique’ fragments can work against you because ‘unique’ often means ‘greater molecular complexity’. One tactic a provider of fragment libraries might adopt is to ensure that analogs of the library fragments are available for follow up screening. There may also be advantages to optimizing libraries for individual assay technologies.
I’ll be at the IQPC compound libraries conference (Duesseldorf, 6-8 Oct) so get in touch (find me in LinkedIn fragment screening group) is you’re going to be there.
IOTA Pharmaceuticals, working with their partners Vitas-M Laboratory, have a commercially-available collection of 5500 fragments, available both in pre-plated library formats and as individual compounds, in amounts ranging from 1mg to 100mg.
If you are interested in hearing more about our 5500 fragments, contact me at david.bailey@iotapharma.com.
Many labs ask us to virtually screen our collection against their targets to stack the deck in their favour and cut down the number of fragments they eventually purchase.
However, I agree with Peter that it's quite good to have several fragments in a collection which recapitulate specific pharmacophores, displaying them in different scaffold contexts. In several of our in-house studies, 1000-fragment screens have allowed us to identify several fragments containing useful pharmacophores, whilst at the same time validating and developing preliminary SAR around the active structures.
The "1000-fragment" library-screening approach is very fast: one experiment can give a rapid appreciation of both druggability (for new targets), and novelty/selectivity (for well-worked targets).
David’s comments got me thinking about the challenges faced by providers of commercial fragment libraries. I can see that screening one’s own library and selling the hits (ideally with crystal structure of target-ligand complex) can make a lot of sense.
However, selling compounds to drug discovery organizations to screen for themselves is a very different business. For starters, you need to reveal structures to potential customers, making it relatively easy for competitors to find out what’s in the library. Secondly, the low molecular complexity of fragments will restrict what one can charge for their supply in a competitive market place. Thirdly, it will be difficult (dare I say impossible?) to get enforceable patent protection for the individual compounds in the libraries.
In the Sept 1 issue of C&E News there is an ad for enamine (enamine.net) offering a fragment library. 1190 compounds from stock, strict adherence to RO3, more than 300 core cyclic fragments, functional group allowing easy modifcation. HTS compounds and building block available for every compound. This seems like a smart business plan.
My personal philosophy on fragments and composition of the library (and I must give credit to Chris Hulme who really was the guy who got me thinking about this at my former employer) is a sparse matrix with appropriate SAR around each node. Essentially, a wide and shallow net.
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