01 June 2016

Fragment library vendors - 2016 version

It's been two years since we last updated our list of commercial fragment libraries, and there have been several changes. The prompt for updating the list is a new Perspective published in J. Med. Chem. by György M. Keserű & György G. Ferenczy (Hungarian Academy of Sciences), Mike Hann & Stephen Pickett (GlaxoSmithKline), Chris Murray (Astex), and me. This covers all aspects of fragment library design, so definitely check it out.

One table in the Perspective compares various libraries, both commercial and proprietary. One of the manuscript reviewers asked if we could evaluate the various vendors, particularly given some negative experiences with commercial compounds. Such direct criticism (and praise!) can be awkward in the peer-reviewed literature, but is more acceptable in an online forum - think of Yelp for library suppliers. Please comment (anonymously if desired) if you've had experiences, positive or negative, with these vendors, and please feel free to add any we omitted.

Note that this list only includes companies that sell their libraries (as opposed to just using them internally).

ACB Blocks: 1280 compounds, 19F NMR-oriented, RO3 compliant, predicted to be soluble, purity >96%

Analyticon: 213 compounds, fragments from nature, RO3 compliant, high solubility, purity >95%

Asinex: >22,000 compounds

ChemBridge: >7000 compounds, RO3 compliant with predicted solubility; minimum purity 90% by 1H NMR

ChemDiv: >4000 3D fragments

Enamine: Multiple subsets including >18,000 RO3 compliant, ~1800 "Golden", and >126,000 with < 20 heavy atoms. Also separate fluorinated, brominated, sp3-rich, and covalent subsets.

InFarmatik: 1700 member consolidated library with different subsets (3D, GPCR, kinase)

IOTA: 1500 diverse, mainly RO3 compliant fragments

Integrex: 1500 compounds with diversity in shape and chemical structure, RO3 allowing one violation

Key Organics: ~26,000 compounds total with multiple subsets including 1166 with assured solubility and RO3 compliant as well as brominated, fluorinated, and CNS-directed fragments

Life Chemicals: 31,000 fragments of which 14,000 are RO3 compliant; also fluorinated, brominated, covalent, Fsp3-enriched, and covalent subsets

Maybridge: >30,000 fragments in total. The 2500 Diversity collection is guranteed soluble at 200 mM in DMSO and 1 mM in PBS.  NMR spectra are available (in organic solvent). It is available in many formats, from powder to DMSO-d6 solution. A smaller 1000-fragment subset is also available.

Otava: >12,000 fragments with various subsets including fluorinated, brominated, and metal-chelating

Prestwick: 910 mainly derived from drugs, RO3 compliant

Timtec: 3200 compounds, structurally diverse with predicted high solubility

Vitas-M: ~19,000 fragments, RO3 compliant

Zenobia:  968 fragments from different design paradigms, cores from drugs, higher Fsp3, flexible cores

9 comments:

Marcos Santana said...

This blog is like and oasis to me! I just started working with fragments and this paper will sure help me out.

Anonymous said...

I am new to academia and starting up a lab that has a heavy fragment focus. I purchased a subset of the Life Chem library that was supposed to have guaranteed solubility up to 200 mM in DMSO. I had LC plate the library in DMSO at 100 mM. we have used the library to screen against three targets and I have noticed there are several wells with precipitate on them.

The library had 50 uL aliquot placed in daughter plates with remaining fragments in the original mother plate for cherry picking. These were stored at -80C and the daughter plates have undergone about 4 freeze thaw cycles.

After reading this paper I don't know if the precipitate is from those fragments not being soluble as advertised or from the freeze thaw cycles. I have now moved the library to a refrigerator and will be taking better care of future libraries based on this paper. This is just my two cents.

Thanks for the insight and I look forward to meeting all the other FBDD researchers in the future. Maybe at FBLD in Boston!

Peter Kenny said...

Just in case it’s relevant, I’ll mention that we observed precipitate in 100mM DMSO stocks when we assembled a large (20k) fragment library at AstraZeneca about 10 years ago. We checked for precipitation (stocks were also shipped to the other three screening centers) before the full library had been solubilized and we noticed that problems appeared to be more likely for salt forms of compounds. We used this information to favor neutral forms in subsequent selections. Slide #19 in this rather dated presentation provides some specific details. Another factor to consider is that DMSO is hygroscopic and it is like to become a less effective solvent for organic compounds as its water content increases.

Peter Kenny said...

Just spotted (after 8 years) an absolute howler in the DMSO solubility slide that I pointed you towards (the ‘precipitate observed’ and ‘precipitate not observed’ column headings are transposed). Looks like we mentioned DMSO solubility issue in our 2009 article which states:

“Solubility in dimethylsulfoxide (DMSO) is also an issue because high concentration stock solutions are used. These were checked routinely for evidence of precipitation after delivery to primary liquid store (PLS) as part of the process of assembling GFS05 in soluble form. Precipitate was observed for 29 out of 525 (5.5%) samples registered as adducts but for only 89 of the 4,440 (2.0%) non-adducts. Most samples registered as adducts are salt forms (e.g., sodium salt; amine hydrochloride) so this observation was interpreted as evidence that salt forms were more likely to lead to precipitation from DMSO.”

Apologies for the confusion

George Bondar said...

I am George Bondar at Life Chemicals. We do have a library of almost 10,000 fragments that we guarantee to be soluble at 200 mM in DMSO. About 7,000 fragments out of these 10K are also guaranteed to be soluble at 1 mM in aqueous media (PBS). We do real solubility tests in analytical lab. This is done at RT. It is possible that a few fragments crystallized out of solution at -80C. It is most likely that this can be fixed by gentle sonication of these samples at RT or even slightly higher temperature (30-40C). Another reason could be that DMSO absorbed a fair amount of water during several melt/open/re-freeze cycles plates went through. A few fragments that are not guaranteed for aqueous solubility could have partially precipitated because of this. I think sonication at 30-40C will help to nicely re-dissolve these few compounds. Please let me know if this worked.

Thank you.

George

Peter Kenny said...

I'm not sure whether sonication is an option for plated samples although George's suggestion makes sense. Something that one might want to think about in the context of freeze-thaw cycles is how quickly the DMSO stocks freeze. If the freezing rate is faster than the precipitation rate then solutes will effectively remain in 'solution' albeit a solid one. If, however, the solute has time to precipitate before the DMSO has frozen, you'll need to coax that material back into solution after thawing. I don't know if this is something that has been discussed or studied.

George, Did you observe any cases of poor solubility in DMSO for particular structural types (e.g. salts)?

Anonymous said...

Thanks for the info Peter and George. The quality of the Life Chem library appears to be everything as advertised we are just learning how to handle it better. As I mentioned, I'm not sure that the precipitation was from molecules that were not soluble but probably from the storage and handling of the library. The paper referenced in the post is quite useful to begin to think about how to handle libraries when you receive them.

Unfortunately, I don't think there is a one-size-fits-all solution to this issue.

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