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.