FBDD in Academia 2

Previously I noted that FBDD provides a means for academic groups (and start ups) to negate the advantage that Big Pharma�s massive screening collections give them. Fragment screening and structural characterisation of fragment binding broadens the scope of a structural biology group�s activities. I do believe that a package of fragment binding modes and affinities is something in which a pharmaceutical company would be interested. But what if an academic group wants to move the fragment hits (which I refuse to call �frits� because I don�t work there any more) further along the optimisation trajectory? I�ll outline some of the issues that need to be addressed and this post is intended to stimulate discussion rather than being a last word on academic FBDD. Please feel free to comment if you�d like to challenge anything or flag up anything that�s been overlooked or oversimplified.

The post-screening phase of lead generation will generally require chemical synthesis. Academic synthetic chemists typically focus on synthesising complex natural products or developing new synthetic methodology so it can be difficult to interest them in the more mundane business of lead generation. To be fair the synthetic chemistry required for lead generation is unlikely to be of sufficient novelty or complexity to earn a graduate student the PhD in synthesis which will be his or her primary objective. There are medicinal chemists in academia but in some cases these happen to be synthetic chemists who think that medicinal chemistry is simply a branch of synthetic chemistry. Also synthetic chemists in academia tend not to be interested in molecular design. The net result is that it can be difficult for a protein structure and fragment screening group to find academic collaborators to take the project into the post-screening phase even when there may be synthetic chemists in the same institution.

As you move from screening to post-screening phases of lead generation the work becomes more multi-disciplinary. Unfortunately �multi-disciplinary� isn�t something that usually gets done well in academic institutions although the problems are often less to do with skills than with organisation (and occasionally egos). In addition to the molecular design and synthesis, it will become necessary to run assays to demonstrate that affinity translates into inhibition of the target enzyme (it�s likely to be an enzyme if you�re doing FBDD). For some targets (e.g. antibacterial or kinases) it�ll be necessary to demonstrate some cellular activity. As you approach micromolar potency you may want to check that compounds in your lead series have sufficient aqueous solubility and don�t have particular affinity for anti-targets such as hERG and CYPs. This is much less of an issue if the main objective is publication but is something to be considered if you�re hoping to flog the results of the work to a pharmaceutical company.

That last comment gets me onto a tough issue for an academic lead generation group. How might you persuade a pharmaceutical company to buy your lead series? The main problem is what you�re trying to sell is information and you�ll need to show that you�ve got something good without giving it away. Life is easier if you own the relevant intellectual property but the synthetic chemistry that needs to get done to secure patent cover is not always going to get people PhDs in synthesis. The other point to remember is that Pharma people may not be willing to look at what you�ve got under a confidentiality agreement because of potential for compromising their own IP position. This can become a serious issue if you�re trying to stake a claim for future activity against related targets (e.g. all tyrosine kinases) or to negotiate exclusivity by preventing a company from using leads from competing programs.

So far this post has focussed on the difficulties (which in Pharma-speak would re-branded as personal development opportunities by the happy-smiley folk who inhabit the HR ether) of doing post-screening fragment-based work in an academic environment. If the primary objective is publication then you can write up at any point that is convenient which means that even a small amount of synthesis can have impact. In contrast, commercial lead discovery organisations need to create a secure IP position before they can publish. When publishing affinities and structures of protein-ligand complexes it�s always worth looking out for results that have relevance that goes beyond the specific project. Examples of synthetic elaboration of a fragment leading to a change in its binding mode are particular relevant and the prototypical (low molecular complexity) nature of fragments means that differences in affinity are more easily interpreted.

Getting pharmaceutical companies interested in the output of an academic fragment project is not trivial. A lot depends on the value of the target and the quality of the leads that have been generated. However, getting to leads requires organisation and realising the value of them requires commercial awareness. Organisation is about persuading people that they�re better off working together and can take time to put in place. Commercial awareness is more difficult to acquire and it�s probably best to try to keep things as simple as possible when starting out. Although this may all seem a bit daunting it�s worth remembering that synthesised compounds will typically be novel and that synthesis can be directed away from known ligands. Also one should not forget the �supporting data� of crystal structures and measured affinities.

This is a good point to wrap up. I believe that FBDD provides an excellent framework in which to both train researchers and do high quality science. FBDD also extends the range of options available to academic researchers for collaborating with industrial partners. That's where I'm going to leave it so feel free to comment if anything that I've said (or not said) has annoyed you.

FBDD in Academia 1

I�ve now gone back to being a tourist and will be in Australia until the end of the month before heading north to Singapore and Malaysia for most of June. Feel free to get in touch if you�re based in either of those countries and would like to discuss fragment stuff or Drug Discovery in general.

Some time ago, I promised to post on FBDD in academia and really can�t keep putting this off. I�ve realised that it�s not going to be possible to squeeze everything into a single post so there should be at least one more post after this one. You should be warned that my academic career ended some years before people started to talk about FBDD so if I appear to be out of touch, it may well be because I am out of touch. Hopefully some of what I�m going to say may be of interest to some of you and please remember that this blog does allow its readers to comment.

I�ll start by making two points, both of which will be obvious to many of you. First fragment based approaches provide a means for drug discovery researchers (both in academia and start ups) to counter the advantages that Big Pharma derives from having massive screening libraries and automated compound handling. Secondly measurement of weak binding and determination of binding mode of weakly bound complexes remains a frontier area in physical biochemistry and biophysics. Remember that the power of a binding assay is defined by the weakness of the binding that can be measured reliably.

An academic group with strengths in protein structure determination and biophysical measurement of binding is well placed to contribute. I see the output of protein structural studies moving away from only determining the structure of a protein to providing a more integrated view of the protein�s �interaction potential�. One point worth making in this context is that measured thermodynamic parameters for fragment binding are particularly useful for developing and validating theoretical models because there are fewer protein-ligand contacts and it is easier to quantify conformational strain. Fragment based approaches also provide a means to validate and explore bioisosteric relationships without the need for a lot of synthesis and I�ve created a graphic showing how this might work.



Assembling and maintaining a usable screening library is likely to be a challenge or at very least an issue for most academic groups. However, a group that has established expertise in fragment screening does have some advantages in negotiating with suppliers of compounds who may value experimental characterisation of how well their compounds have behave under assay conditions. Vendors of specialist fragment libraries really should value this type of feedback and if they don�t they shouldn�t be in the business of marketing fragment libraries. I sometimes wonder if synthesis of fragments might form the basis for final year undergraduate synthesis projects which could be quite self-contained and include a molecular design component. In passing I�ll pose the question to readers from academia as to whether they think they�ve got molecular design adequately covered in courses at their universities although I�ll have to leave this topic for another post.

As we all know there is more to FBDD than fragment screening. Once you�ve found fragments that bind, tested analogues of these and determined crystal structures, you�ll need to do some synthesis. For a group whose main expertise is characterising binding and protein structure determination this may a good point to bail out and prepare the results for publication. A group with some access to synthesis may wish to take the project a bit further and publish once they�ve observed some SAR. One of the attractions of FBDD for academic researchers is that there are a number of points at which they can choose to write up the project for publication. It is also worth pointing out that FBDD provides an excellent framework to gain understanding of molecular properties and interactions between molecules. This understanding is essential if you�re planning to do molecular design the basis of which is manipulation of these properties with predictable results.

What if academic researchers want to take things further and generate lead series that will be of interest to Pharma? Synthesis will be necessary and life will get more complicated. I�ll pick this up in the next post (Kakadu salties permitting) since there�s quite a bit to say and I�m actually still thinking about this.