Friday, 20 March 2009

Fragment Library Design

The first law of computing (garbage in, garbage out) applies equally well to screening fragments. Selection of compounds for fragment screening is a theme that I will explore in some depth in future posts. For now, I'll just let folk know that we have already compiled some literature on the topic and that our article on this topic is now available 'online first' at the Journal of Computer Aided Molecular Design. Three of my friends and I put this together as a contribution for the special issue of this journal on FBDD so you can expect to see more articles on the subject appearing soon.

There's going to be some fragment action at the ACS. Mel will be there so look out for her.

Literature cited
Blomberg et al, Design of compound libraries for fragment screening, J. Comput.-Aid. Mol. Des., in press (online first) DOI

Sunday, 8 March 2009

RSC BMCS Fragments 2009

| next >>

It is during the opening remarks for the RSC BMCS Fragments 2009 Conference that I think to myself that Stalin anticipated the emergence of high throughput screening with his comment, ‘Quantity has a quality all of its own’. Fragment based methods can be seen as representing an attempt to re-introduce manoeuvre to a battlefield that is increasingly dominated by grim attrition and the intellectual property tar pit.

More than one speaker notes the relative maturity of FBDD although I am struck by the high mission statement to results ratio for more than one presentation. I am also struck by the relatively narrow range of targets that appear to be getting tackled. I can’t help thinking that a realistic survey of the target class scope of FBDD would not have been out of place in this program.

There are three talks that I particularly like. Rod Hubbard (University of York | Vernalis) starts his presentation with a look at some of the ‘pre-history’ of FBDD (e.g. GRID | MCSS | MSCS) and notes the increased use of surface plasmon resonance (SPR) to detect fragment binding. I am really pleased to see this ‘pre-history’ mentioned because we’ve done something similar in the introduction to our article on fragment library design that is currently in press in JCAMD. In some ways this would have been a good talk with which to start the conference rather than finish.

Mark Whittaker (Evotec) shows how biochemical assays (see lit) can be used screen fragments and stressed the need for orthogonal detection methods (e.g. NMR) to ensure that activity is real. The Evotec group use a range of fluorescence experiments to quantify and characterise binding and appear to also have significant expertise in design and maintenance of fragment libraries.

One personal highlight of the conference is that I finally get to meet Dan Erlanson (Carmot Pharmaceuticals). Dan runs the Practical Fragments blog with Teddy Zartler and he does an excellent talk on fragment-based chemotype evolution. The idea is to build a reactive group into a fragment that binds (the ‘bait’) and allow this to react with library compounds while it is bound to the protein. The target protein effectively selects the combinations of bait and library compounds that bind most strongly to target and sulfur chemistry (disulfide formation; displacement of halogen) is particularly useful. This probably reflects ease of reaction in aqueous media and similarity of reactant and product hydrogen bonding and charge characteristics when sulphur chemistry is used.

I am surprised that there are no talks on selection of compounds for fragment screening. The rule of 3 gets frequent mention and but at least my ‘efficiency metric fatigue’ is not aggravated by a presentation devoted entirely to the topic. I am refreshed by the fact that David Banner’s (Roche) talk makes no reference to ligand efficiency. David makes reference to ‘needle screening’ which represents an alternative way to think about molecular complexity, although the Roche folk never used the term when they introduced the idea in 2000. As a physical-organic chemist, I am also refreshed by Nino Campobasso’s (GSK) comment that FBDD gets folk thinking more about the molecules and, in some ways, represents a return to traditional medicinal chemistry.

The conference has its amusing moments and we particularly enjoy Molecular Simpleton’s attempts to extract information from Vicki Nienaber. No doubt they run an ‘Interrogation Styles’ course where Molecular Simpleton works and it will be no surprise if he finds himself booked on it.

The conference concludes shortly after Rod’s presentation and I leave, wondering about how broadly applicable FBDD really is. Targets that bind ATP are relatively easy to hit with fragments especially if you’re not worried about physiological ATP concentrations. A number of serine proteases can be nailed with something as small as benzamidine at concentrations that are well within the reach of standard biochemical assays. However, there are plenty of interesting targets that do not recognise adenine or arginine. I guess that time will tell and hopefully a clearer picture will emerge at Fragments 2011.