Boston is a beautiful city, and I am staying in a beautiful and merry location, Faneuil Market. Lots of good grub, charming old marketplace with cobbled stones, and history written at many places around. Boston Harbor right after crossing one road. Lovely.
But anyway, on to the conference highlights. Since I am a little pressed for time over these two or three days, I will simply briefly mention some of the more interesting stuff and observations and leave the details and links (of which there are many) for later.
1. There was almost unanimous agreement about the role of modeling in modern structure based drug design (SBDD). There were some who rightly questioned the exact value and utility of different kinds of modeling, but no one who thought it was not helpful. The real problem is not really of synthetic chemists appreciating modelers (although that is a problem in some cases) but of there being something of an educational gap between modelers and chemists. The consensus was that both camps simply should not see each other as competitors and/or as witch doctors. There should be vigorous discussion between the two and especially outside formal channels. I don't think there were more than one or two drug design projects which did not involve some component of modeling. It's a pretty encouraging scenario, but of course there's still a long way to go, as there always seems to be in drug discovery.
2. One of the most enlightening sessions for me was a roundtable session with one of the leading computational chemists in the world and probably someone who is more familiar with docking as well as other drug discovery related computational methods than anyone else- Richard Friesner of Columbia and Schrodinger. Friesner expressed surprise about large companies not investing more in computational resources because they somehow think it's so "risky". He pointed out that the costs for implementing even a big computing grid are probably a fraction of the cost invested in HTS, RNAi and suchlike, many of which also turn out to be big risks. The take home message really is that experimentalists should be bold and should come ahead to test docking programs for example. Friesner also cited the success that pharma has had with Schrodinger programs using their libraries. Unfortunately, this knowledge is proprietary. More needs to come forth for academia and collaboration.
3. David Borhani from Abbott gave a nice talk about their Lck kinase inhibitors, which also led to discovery of selective Hck inhibitors. A single hydrogen bonded interaction was responsible for conferring the selectivity.
3. Mark Murcko, CTO of Vertex, gave a general overview of SBDD and where it has come. He pointed to some of his favourite examples, including carbonic anhydrase, HIV protease, and of course Vertex's newest HCV protease inhibitors.
4. Arthur Doweyko from BMS invented a whole new solvent system cryptically named "Q" for selecting good poses. He rightly opined that it's actually good to separate the docking and scoring problems, and address them separately. His "Q" basically deals with calculating the hydrophobic effect based on hydrophobic solvent accesible surface area (SASA). He showed cases where the "simple" correlation between SASA and affinity prediction (or deltaG) failed. This was because in traditional SASA calculations, the probe chosen is often water, with a diameter of 1.4 A. which misses some of the fine nature of the lipophilic surface. Doweyko mentioned that in some cases, simply changing the diameter of the probe to 0.5 A gave better correlation.
6. Gergely Toth from Sunesis talked about their well-known tethering disulfide approach, combined with computational approaches that included conformational searching of the tether conformational space and MD.
5. Not surprisingly there was lots of discussion about kinase inhibitors, with many technologies and protocols directed towards finding selective compounds. While allosteric inhibitors promise new frontiers, traditional ATP competitive inhibitors are still popular targets.
6. Other speakers included structural biologists, chemists, modelers, crystallographers, and "informaticians" from Novartis, Bayer, Lilly, and Pfizer among others. Much discussion and musings especially on modeling, HTS, crystallography.
All in all, I am having a nice time. Tomorrow's speakers include Rich Friesne and Roderick Hubbard (Vernalis) among others.