28 October 2013

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.  


Dan Erlanson said...

Thanks for the summary. Did Matthias discuss how Merck uses their thermodynamic data? There has been quite a debate over the past few years, with some suggesting that enthalpically-driven binders are superior while other research suggests that subtle changes to the molecules can cause such major changes to the thermodynamic parameters that the information is not particularly useful.

Dr. Teddy Z said...

Thermodynamics was definitely a hot topic of discussion. I have not summarized all talks into coherent topics, but I definitely recollect people making statements about enthalpically vs. entropically driven binding. As I find them, I will highlight them.