Who's Doing FBLD, 2014 Version

It's been a while since we updated this list.  The first list had 24 companies, the second 44.  From 2011 to now, what's changed?

I have divided the list into (primarily) providers of services and pharmaceutical companies. This does not mean that that providers don't do their own discovery, or work in a mixed-model.  I have annotated those companies which were not previously on the list.  Please note that this does not necessarily mean they were not doing FBDD previously, they just were not listed.If we missed someone, let us know and we will update the post.

Providers:
Ancorex  (New 2014)
Beactica
Biodesy  (New 2014)
Biofocus(Galapagos)  Acquired by Charles River Laboratories
Biosensor Tools
BioSolveIT
Chemical Computing Group   (New 2014)
Crelux
CrystaX Pharmaceuticals  Acquired by Oryzon Genomics
Domainex   (New 2014)
Emerald BioStructures
Exscientia   (New 2014)
Evotec
Graffinity  Acquired by NovAliX 
iNovacia  Acquired by Kancera
Infarmatik
Intellisyn (New 2014)
IOTA Pharmaceuticals
Kinetic Discovery
MEDIT
Molsoft (New 2014)
Nanotemper (New 2014)
NMR Research  (New 2014)
NovAliX
Pharma Diagnostics
Proteros 
Pyxis Discovery  (Are they still an ongoing concern?)
Red Glead  (New 2014)
Saromics (New 2014)
Schrodinger
Selcia
SensiQ  (New 2014)
Structure Based Design
Viva Biotech  (New 2014)
Zenobia Therapeutics
ZoBio

Companies: 
Abbvie             split from Abbott
Amgen             (New 2014)
Ansaris (previously Locus)
Ariad               (New 2014)
AstraZeneca
Astex              Acquired by Otsuka(2013)
BioLeap
Boehringer Ingelheim
Bristol Myers Squibb
Carmot Therapeutics
Constellation Pharma
Crown Biosciences 
Dart Neuroscience
Eli Lilly
Genentech (Roche)
Genzyme Acquired by Sanofi-Aventis
GlaxoSmithKline
Heptares
Johnson & Johnson 
Merck
Nerviano Medical Sciences
Novartis
Pfizer
Plexxikon    Acquired by Daiichi Sankyo (2011)
Polyphor
Roche
Sprint Bioscience
Takeda California
UCB   (New 2014)
Vernalis
Vertex

**UPDATE** 27Mar2014: added Domainex, UCB
**UPDATE2** 28May2014: added MolSoft, Ancorex

Biophysics in the Alsace

Two weeks ago, the first Novalix conference on Biophysics in Drug Discovery was held in Strasbourg.  I was lucky enough to be one of 160 people in attendance (this was largely a european affair, with ~10% of attendees from outside the EU).  The split of attendees was 60/40 industry/academia.  The conference was split into four themed sessions: Biophysical characterization, Mechanistic Analysis, Emerging Technologies, and Biophysical Methods for Identifying Hits and Leads.  This was not a fragment conference, but many of the talks were specifically about fragments, and the rest could be impactful in fragments.  I want to share my impressions/thoughts on the speakers relevant to the readers here.  You can also go to my website to see my thoughts on the speakers not relevant to FBHG. 

Michael Hennig- Roche: His talk discussed the various methods and showed examples for each.  This was a great talk giving a great overview of the various methods available for active follow up.  Specifically fragments: The Roche fragment library is ~5000 compounds.  In terms of QC, 80% of the samples show >85% purity (by LC-UV-MS).  Purity of fragment libraries has been discussed here previously.  For Roche's uses, every fragment hit is followed up by MC and NMR, so a lower threshold of purity will not have a negative impact.  He also presented results from a 2D-HTS.  This was a new concept for me and I found it intriguing.  The basic concept is to graph the results from two screens (or related proteins) to identify compounds that activate one, but not the other, or activate one and stimulate the other, etc.  He also presented direct and in-direct methods using Mass Spec methods.  To me, this area was one of the more fascinating areas discussed at the conference.  Theoretically, this could be applicable to fragments, but I would really like to see specific applications.  Lastly, he spoke on biophysical methods and membrane proteins. 

Rob Cooke- Heptares:  He presented the STaR approach that has been widely published and presented here, here, here, and here.  The talk was very similar to other talks that Heptares and Rob have presented in various fora over the past year.  The main thing that I was taken by was that there was no mention of NMR.

Matthias Frech - Merck: I really enjoyed this talk.  One of the main things I noted was his use of the phrase "hit affirmation".  Confirmation (according to the dictionary) is a piece of corroboration, while affirmation means it is true.  Is this parsing meaning where none exists?  Maybe, but I think it may also inform on mindset.  He said that SPR is the workhorse for FBHG, but they also use NMR, MST, ITC, stop-flow, and X-Ray.  95-98% of their projects are accomplished using SPR and ITC.  However, he stated that SPR is used to rule out compounds, not rule them in.  This is key to the proper use of SPR.  I would be interested to see if anyone else takes this approach.  They use SPR and ITC to obtain the enthalpic and entropic terms for compound binding.  ITC yields the enthalpy, SPR yields the DeltaG et voila, simple math (my favorite kind) yields the entropic term.  One other very interesting item that he noted was that there was no correlation between affirmation rate and target class for 31 projects they undertook (2009-2012).  

 

Tomorrow I will update the Mechanistic Analysis session.  

To have shape or not?

I consider the debate/discussion/civil discourse on what/where/when/why/how of 3D fragments to be one of the most interesting topics in the fragment field right now.  A paper has come out from the 3Dfrag consortium.  The first take away from this paper is we have a NEW acronym, FBHI (Fragment-based hit Identification).  Their central thesis is that fragments are too flat for certain target classes of targets, thus resulting in too low hit rates. This paper describes their efforts in pre-competitive space to prove/disprove this hypothesis.  It's fascinating.  

Using the nPMI as their metric for "3D-arity" they compare 1000 fragments representation "commercial" space to Zinc InMan Compounds fragmented by RECAP.  It is obvious that InMan has more 3D-arity, but the question is always, is this biased by target type of compound type (like natural products)?  But, to the greater point, will 3D fragments give better hit rates than 2D for certain target classes?  Many people point to the Hann complexity model a (MIP) and say no, because there is more potential "bad" interactions.  However, the authors point out if the NUMBER of sites of interaction is the same, this should not be the case.  Recent data from Evotec seems to support this they state. 

The 3Dfrag consortium's goal is to explore the role of "3D-arity" in fragment screening success.  As shown in this figure, they apply pretty standard selection rules for their collection, including the Pfizer Rule (medchemists inform on the final selection process).  

Interestingly, even after all of this, trying to select for "3D-arity", 70% of their final 200 molecules were largely flat (nPMI1+nPMI2< 1.1).  Making matters worse, 10% of the compounds could not be delivered by suppliers and 5% failed QC (by NMR). The nPMI and maximum similarity is shown below for 170 compounds.  For the maximum similarity, a right-shifted plot shows a high degree of internal similarity, while left-shifted would be more diverse.  So, it appears that their library is diverse (most compounds < 0.8).  Importantly, of the 170 compounds, they appear to fill a much wider region of 3D-space.   

One of the tools generated by the consortium is 3Dfit, a webtool that is free and allows fragments to be evaluated.  They generate up to 9 conformers (blue to red, low to highest energy) that are then plotted on the PMI triangle.  They also calculate a radar plot of molecular properties:

Molecules outside the consortium's GUIDELINES are flagged for consideration (see (b)).  The consortium has now undertaken chemistry to generate additional 3D fragments.

As the authors state:

We believe that this strategy will build a library with broader coverage of biologically relevant chemical space compared with current fragment collections and the identified hits will offer higher-quality start points for medicinal chemistry projects.

They will now experiment and try to validate (or invalidate) this hypothesis.  But, as they point, these sorts of Pre-Competitive Initiatives have difficulty getting buy in from partners willing to devote time, resources, assets to this.  They are looking for more people to participate.  I have no skin in this game, but I would love to see people step up and help this initiative prove/disprove a crucial hypothesis in Fragments.

What you are Missing.

The nice part about blogging is you can post anything you want.  Mostly, we post on interesting (to us at least) papers, news about fragments, conferences, and so on.  We have assiduously avoided being a commercial outfit; what we post is what we believe in and we don't post for cash or barter.  So, we tend to not promote people/companies.  I am so totally breaking that rule right now.  

Many of you probably know Chris Swain, the principal of Cambridge MedChem Consulting.  [Full Disclosure: Chris and I have worked and published together.  I hope that does not diminish your feelings about him.  :-)] If not, this post will introduce you to him and the many wonderful resources he curates, particularly in the FBHG world.  There is so much there, sometimes I forget what he has; in fact, Chris's site goes by the rule, "Why make them buy the milk, give it to them, and the cow too!"  

One of the great resources Chris has is a graphical snapshots of a metric pile of fragment collections.  On Monday, Chris added nPMI (Principal Moment of Inertia) to these snapshots.  As has been discussed some, I (and Justin Bower from the Beatson) think this is the best way to evaluate "3D-arity".  It is interesting to just browse through the snapshots.  Some of the collections that are VERY large do seem to have a good to excellent amount of 3D-arity.  Does this correlate with increased hit rates for certain target classes?  

Well, Chris has thought of that.  He has been collecting the compounds from the literature that are reported as fragment hits.  He has just updated that snapshot with nPMI also.  What do the reported fragment hits tell us?  I would say that the vast majority of the reported fragments are Voldemort Rule compliant.  No surprising.  What I would like to see is a breakdown of fragment property against target type.  This may the part of the cow Chris isn't giving away.  There may be other slices/dices too.  

Trust me, go and spend some time on Chris site.   I won't call it a time waster, but it will suck you in.

Fragments in Living Cells

GPCRs seem to be popular around here lately.  In this paper, a group of researchers in the UK developed a report-fluorescent assay to be used on living cells to screen fragments.  Recent advances have been made in structural studies of fragments (see Receptos and Heptares) and with this new assay, the entire suite of experiments for prosecuting FBHG exist for GPCRs.  As the authors point out, and I mentioned here, mucking around with GPCRs with things like detergent stabilization removes ancillary proteins which can provide allosteric interactions. As the authors state:

It is now acknowledged that GPCRs can adopt multiple active conformations as a consequence of protein-protein interactions that can lead to the activation or attenuation of different signaling pathways.  Furthermore, different agonists appear able to bias signaling in favor of a particular downstream pathway, including those that do not involve heterotrimeric G proteins . It is also clear that the binding affinity of antagonists can vary depending on the signaling pathway and agonist that is being studied. These data suggest that intracellular signaling proteins can elicit marked allosteric influences on the binding of both agonists and antagonists to a particular GPCR and as a consequence the cellular context in which binding affinities are measured will have a major impact on drug screening strategies. [Emphasis mine].

To build their assay, they used an existing fluorescent existing amine congener that was commercially available and ensured that it had competitive, antagonistic properties against A3AR (Adenosine-A3 receptor).  It exhibited many desirable characteristics for a high-content screening: including high affinity and slow off-rate.  It was able to quantify agonist displacement from A3AR.  

To test for the ability to detect weak binders, they deconstructed the high affinity A3AR antagonist (1) into its component fragments (2-7) [the affinity values are pKi].  They then acquired a 248 subset of the Maybridge fragment library that was Voldemort Rule compliant.

  They found 38 confirmed actives, with the compounds shown below as the top 6:

To me, the interesting part of this paper is NOT the subsequent SAR and the novel compounds that resulted, but instead the fact that there is now an assay for A3-and A1AR that can reliably detect fragments and support SAR studies.  Of course, one major caveat here is something that I learned from a venerable GPCR chemist at Lilly: the natural ligands of GPCRs are fragments, so of course fragment screening works.  I think most people who work in fragments would be very happy with 1 microM actives from a screen; I think most GPCR chemists would not.  I would also imagine that ligand efficiency is even more important when working in this class of compounds.