I recently returned from Philadelphia, where the American Chemical
Society held its 244th national fall meeting. As always this was a
massive affair, but fragments were well-represented, particularly in a nice
session organized by Percy Carter, Debbie Loughney, and Romyr Dominique.
I opened the session by giving an introduction to
fragment-screening, as well as an overview of some of the work we’re doing at
Carmot. Andrew Good had perhaps the best title (“Fragment fat wobbles too”),
and discussed some of the work done at Genzyme on Pim-1 kinase. Eric Manas next
described some of the computational tools being used at GlaxoSmithKline, in
particular strategies to deal with water. He also discussed the utility of
looking for fragment analogs early in a project. In the last talk before the
intermission, Chris Abell from the University of Cambridge described a number of
projects from his group, starting with antimicrobial targets (such as this one); we’ll cover another in a separate post. Chris is unabashedly going after
difficult targets, not just protein-protein interactions, but oligonucleotides
– specifically riboswitches. There is only limited precedent for targeting RNA
with fragments, so it will be fun to see how this progresses.
Francisco Talamas next described a nice example from Roche
using FBLD to discover hepatitis C NS5B Palm I allosteric inhibitors. An HTS campaign
of around 900,000 molecules yielded just 3 hits, none of which were advanced. A
fragment screen of about 2700 fragments gave a better hit rate (5.9%), but of
the 29 co-crystal structures attempted only a single structure was obtained.
However, by combining the information from this crystal structure with
information from other crystal structures, both proprietary and public, the
researchers put together a set of rules to design a de novo fragment library tailored to this protein. This effort
ultimately yielded compounds that were optimized to a clinical candidate.
Next, Nick Wurtz from Bristol-Myers Squibb described his
company’s approach to discover neutral Factor VIIa inhibitors. The researchers
used a combination of computational, functional, and biophysical approaches to
find uncharged fragments that would bind in the P1 pocket, leading to a couple
dozen crystal structures. Despite the low affinities of these fragments
(typically mM), many of them could successfully be merged onto an existing
series, replacing a positively charged moiety to yield potent molecules with better permeability. This is the first time I’ve seen a fragment story out of
BMS, so I'm glad to see that they’re active in this area. This is also a prime
example of what has been described as fragment-assisted drug discovery.
Finally, Prabha Ibrahim of Plexxikon gave a lovely overview
of the discovery and development of vemurafenib, including a more detailed
description of the SAR than has been presented in their earlier papers.
In addition to this dedicated session, there was a
scattering of other talks and posters, including a notable poster from Timothy
Rooney at the University
of Oxford using
fragment-based approaches to discover bromodomain inhibitors, a target class
we’ve previously discussed.
A session entitled “A medicinal chemist’s toolbox” ranged
over several topics of interest. Ernesto Freire of Johns Hopkins gave a great
overview of thermodynamics in drug discovery, a topic we’ve previously covered.
Most readers are probably familiar with the concept of enthalpy-entropy
compensation, in which (for example) an added hydrogen bond fails to achieve
the desired boost in potency due to unfavorable entropy. Recognizing this, he
suggested that one should target groups in proteins that are already
well-structured, so you don’t have to pay the cost of structuring a disordered
part of the protein. He also suggested that if you introduce one hydrogen bond,
you might be better off introducing a second one too, as the incremental
entropic cost is likely to be low.
György Keserű of Gedeon Richter discussed the importance of
avoiding lipophilicity by using tools such as LELP, which we’ve covered here
and here. Continuing this theme, Kevin Freeman-Cook of Pfizer described two
examples of using LLE in lead discovery programs, in particular calculating LLE
values before making compounds. Although this may seem obvious, what was quite
striking was the dramatic effect subtle changes in structure could make to ClogP
values.
Of course, these are just a few of thousands of
presentations. Please feel free to point out any that caught your eye, or expand
on some of those mentioned above. And just a reminder, it’s only 4 weeks to FBLD 2012
in San Francisco – the biggest fragment event of the year!
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