Dan and I are were at the CHI Discovery on Target meeting last week. It is highly focused on target validation and early stage hit generation. This is NOT a chemistry conference, although there were plenty of chemists and chemistry talks; the target audience is biologists. As such, it was a great arena to be teaching about fragments and educating a whole different phyla of FBDD consumers. It was also nice to meet people and have them say, "Oh, I love the blog." Of course, I just say, try commenting, that's manna to bloggers. The nice thing is people generally understand FBHG, unfortunately I think they generally misunderstand it. Why?
I think part of the problem is that the Most Impactful Papers (MIPs) in the field are also the Most Destructive Papers (MDP) in the field. So, what are the MIP for this field? For me, the criteria are pretty straight forward: one or two papers that are seminal to understanding the field. As you may already be guessing, my list of MIP intersects my MDP.
Most Impactful Papers:
The Rosebowl of Fragment Papers: SAR by NMR. This is the paper that showed that NMR was not bound by doing structures, but was a viable screening paradigm. It started the whole "Fragment" thing.
- The Rationale Behind it All: The Leach and Hann Molecular Complexity paper. If I had one paper to give to someone to explain why you should use fragments, this is it. The first three graphs should be in every introduction to FBHG.
- The Voldemort Rule: The Rule of Three paper. This paper has defined what a fragment is for a decade.
- Fragments get a name (that's never used): Fragonomics. OK, self-referencing is not cool, so this should really be Dan's paper, the first review on FBDD.
- Pfizer lifts the curtain: Pfizer's fragment library paper. I love this paper because it gives a great overview of how Big Pharma put its fragment library together (think laser pointers!).
This is obviously a very short and incomplete list, and totally my opinion. Let me know what you think MIP are in the comments.
So, what are "destructive" papers? Those are the papers that require me to spend a lot of time explaining why what people understand is not really a good general, practical approach.
Most Destructive Papers:
- I think THE most destructive paper is also the most impactful: SAR by NMR. How can that be you say? Easy. Because of this paper, the vast majority of people who "have heard" of fragments think that you need to label protein to do use NMR for fragments. While, target-based screening is really powerful, I don't think it should be the first thought for screening, but is more impactful on active follow up. I can here the counterarguments coming, but WAIT there's more. They used linking, rather than growing. I think most people would agree that this is the "Serendipity" approach. I think this territory is well trod on this blog. Lastly, warheads.
- While it had its place the Rule of Three paper has also become destructive. This is a "hot" topic, but my main problem is the slavish devotion to an empirical "Rule".
I am also cross-posting this on my site http://www.quantumtessera.com/325/ and the LI group to see if maybe a different venue will generate more comments.