Break

I am in Boston for a kinase inhibitors conference this week, so I may not be able to blog, except when I want to complain about some kinase inhibitor speaker. Enjoy the fall.

Boston ahoy. Pharma ahoy.

(Above: The view across the bridge at the World Trade Center and Below: The always scenic view across the Charles in front of MIT)

I am finally back from a trip that was both professionally and personally immensely satisfying. I can keep on talking about how great a place Boston is- the place where I stayed and the historic places cruise I took around the harbor were just fantastic- but my praise has also been somewhat tempered by two realisations. Firstly, the boss paid the tab which makes it a little easier to have a good time. Secondly, everybody says that it's only in these four months that Boston is the best place on earth. Anytime after that and the enjoyment quickly starts to dwindle because of the pretty nasty weather. So if I could get a part time dream job where I could work in Boston only for four months, that really would be it. Dream on.

One of the good things about this conference was that our patent on a new (potential) anti-cancer compound just got filed days before the conference. That made it possible for me to present the work. The work was well-received, although as is always the case, there's miles to go before we can possibly sleep.

The conference itself was great, and it was held in a scenic location- the World Trade Center by the side of the harbor (although almost everything in Boston seems to be harbor-side). It was the first time I got a preview of what it's like to work in industry. I was happy to see that a camarederie similar to that among academic scientists exists in the pharmaceutical industry too. However, I also got the feeling that that camaraderie is more guarded, and also a little more exclusive. I may possibly have been the only graduate student there among about a hundred participants. I was also surprised to see, perhaps not so surprisingly in retrospect, that folks in industry do almost exactly the same kind of work that we do, at least in the very initial stages of drug design. But where they really get a head start is in validating early models by having massive in-house facilities and personnel for things like pharmacokinetics (investigating the properties of the drug in the body) and x-ray crystallography (having a structure of the drug bound to the protein which it is supposed to inhibit). So they can decide relatively early on whether to pursue or drop a prospective candidate. We are now planning to put our own compounds in animals, and I would have given anything to have a crystal structure and pharmacokinetic data in the early stages when we had the lead. Pharma can do this, and they learn a lot from it.

The downside of working in pharma? You cannot talk! About 60% of the presentations in the conference did not have a single chemical structure in them. In most cases the only structure displayed was an already well-known one. It's really frustrating to be a chemist and not see what are the structural characteristics that are leading to all those tantalizing pieces of biological and clinical data. And it looks like it's only going to get more proprietary. That's the only thing that makes me a little wary of working in pharma, the fact that you often cannot talk to people outside even if you know that they could have the answers to your questions. Also, the fact is that many of the technologies that are now roaring in pharma have their origin in basic science developed in academic labs. I always keep on imagining how much the science--->technology transit time would have been reduced if there could have been collaboration between pharma and those academic labs in the initial stages. Of course there are IP issues, but one cannot help but think about this.

But all in all, a very fruitful experience. Unfortunately I missed getting aboard Paul's grand tour of Harvard Chemistry (although I heard some really good piano in the chemistry lounge), but I look forward to seeing more of everything next year.

SBDD Boston 1

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.