Pete Kenny is always ahead of the curve, and so despite his
absence from the conference he did put together a nice preview. He worried that
the big pharma talks might be “strategy-heavy and results-light,” but happily
this was not the case. In particular, Jane Withka gave a very detailed talk on
Pfizer’s carefully constructed fragment library (see also here). One statistic
that caught my eye is that, after screening this library against 21 proteins,
44% of the 2500+ fragments have hit at least one target – considerably higher
than the 33% that has been seen in several organizations. Whether this is
because of a better library or simply more screens remains unclear.
Fragment validation – or the lack thereof – and fragment
promiscuity were also frequently recurring topics. Peter Kutchukian from
Novartis observed that frequent hitters are not always problematic: fragments
that hit multiple targets were actually more
likely to produce co-crystal structures than more selective fragments.
There were lots of cool approaches for finding fragments;
one particularly impressive advance was presented by SensiQ in a workshop
before the main conference. Their surface plasmon resonance (SPR) instrument
operates as expected; what sets it apart is a cunningly designed injection
method in which the sample compound flows through a long capillary before
entering the flow cell. A concentration gradient forms within the capillary,
and by controlling this gradient the user can run a full dose-response curve
over several orders of magnitude without
having to pre-dilute the sample. Instead of doing a primary screen at a
fixed concentration and then following up on active compounds, dissociation
constants can be determined directly from a primary screen.
Protein flexibility is a subject dear to my heart, but not
typically observed in biophysical fragment-finding techniques besides
crystallography and protein-detected NMR. Josh Salafsky described Biodesy’s
second-harmonic generation technology to specifically find molecules that cause
conformational changes. More surprisingly, Beactica’s Helena Danielson argued
that SPR could be used to observe conformational changes in membrane proteins. Although
I’m no SPR expert, I've only seen the technique being used to detect changes in mass, so it will be fun to see how this develops.
Fluorine NMR looks like it’s finally coming into
its own; Brad Jordan discussed how this has become a standard screening
technique at Amgen, and both Nino Campobasso (GlaxoSmithKline) and Stephan Zech
(Ariad) mentioned that their companies are using it too.
In addition to the method talks there were plenty of
hit-to-lead and success stories, some of which have been covered on Practical
Fragments, and some of which will be as the publications come out.
If you weren’t able to make it this year, FBLD 2014 is
tentatively planned to be held in Basel,
Switzerland.
And if you can’t wait that long for your next fragment fix, there is at least
one more relevant event this year and several already taking shape for 2013 –
details to come shortly.
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