03 April 2013

Everything that can go wrong

Anyone who ventures into fragment screening will encounter problems. Maybe your compound isn’t what you think it is. Or it’s contaminated with something that mucks up your assay. Or it degrades – possibly during the experiment.

Maybe you haven’t removed the PAINS from your screening collection, and you get results like this. Or perhaps you forgot to add detergent, and your hits are all aggregators.

Even if all your compounds are pure and beautiful little three-dimensional works of molecular art, things can go wrong in screening. As part of our occasional “Getting misled” series, we’ve highlighted problems that can arise in NMR and crystallography (here, here, and here). But that doesn’t mean that practitioners of SPR, ITC, thermal shifts, or other assays can relax.

As the old saying goes, forewarned is forearmed, so Ben Davis (of Vernalis) and I have put together a brief review of the many things that can go wrong in fragment-based lead discovery campaigns; thanks also to readers who shared their horror stories. It has just been published as a Digest in Bioorg. Med. Chem. Lett. To maximize readership, Elsevier has agreed to make this open access, at least through 2013. We hope this will be useful for folks starting out in the field, as well as for other researchers, journal editors, and reviewers trying to assess and build on the literature.

Of course, I’m sure we’ve left out lots of things that can go wrong, so feel free to comment here!


Dr. Teddy Z said...

I am going to read this today, but your "brief" review is 9 pages! :-)

Macdonald said...

A very good piece, made a very good read for a PhD student working with fragments!
I did raise a wry-smile though when after reading about the PAINS inhibitor SJ-172550, I noticed a link on the side of the page to this compound being sold by SigmaAldrich... sigh. This isn't a story I'd come across before, but just looking at it does make even a junior chemist in the field raise my eyebrows!

Luca S said...

A very interesting paper, especially for what concern detergents and the optimization toward aggregation.
I'd like to have your opinion, and a review in the blog if you think appropriate, about my recent article "From Small to Powerful: The Fragments Universe and its Chem-Appeal"

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