The first event on our 2010 calendar, the Molecular Medicine Tri-Conference 2010, was held in San Francisco earlier this week. There were fragment talks and a roundtable, as well as a number of vendors selling fragment libraries – we’ve recently noted how rapidly this area has expanded.
Michael Hennig presented a nice overview of the history and development of fragment-screening at F. Hoffmann-La Roche (Basel). Work done there back in the late 1990s relied on NMR and crystallographic screening of a library of 300 fragments, described in the seminal “needle-screening” publication in J. Med. Chem. Today that library has grown to 6000 compounds following a relaxed rule-of-3 (allowing in particular more hydrogen-bond acceptors and higher lipophilicity) and requiring at least one hydrogen bond donor or acceptor and at least one ring. Also, the primary screening technique is now surface-plasmon resonance (SPR), with crystallographic follow-up; the entire collection can be screened on a single Biacore instrument in four weeks.
Hennig shared two case studies, one on BACE-1, the other on chymase. In the second case, a dozen fragments were successfully co-crystallized with the enzyme, and all but one of these bound in the S1 pocket, revealing the importance of this site for binding. In response to a question about how widely FBDD is used at Roche, Hennig said that it is applied to all targets that are technically feasible.
In another talk, James Madden described fragment-based discovery at Evotec. An increasingly stringent series of assays (from high-throughput high-concentration functional assays, through SPR and/or ligand-detected NMR, and finally crystallography and/or protein-detected NMR) helps keep the number of compounds manageable at each step. Madden also presented two cases studies, BACE-1 (clearly a popular target for FBDD, perhaps due to its intractability to many other approaches) and PDE10a.
A fun talk with relevance beyond FBDD was “Examples of X-ray Bloopers”, by Edward Kesicki of the Infectious Disease Research Institute (IDRI) in Seattle, WA. He described several cautionary tales from his own experience. In one case, a chemist provided the structure of the wrong enantiomer to a crystallographer, who duly refined the data, resulting in weeks of confusion and time-consuming follow-up experiments. In two others, crystallographers inadvertently omitted methylene units in fitting electron density. We’ve previously commented on the dangers of taking crystallographic data at face value, and Kesicki also mentioned an effort by Stephen Warren of Gonzaga University to comb through and correct structures in the protein data bank. He has a lot of work to do: of the 1000 structures examined thus far, roughly 20% have problems with the ligands.
Finally, in a panel discussion on “medicinal chemistry drivers,” someone asked about the role of fragment-based drug discovery. Consistent with the idea that fragment approaches are becoming increasingly integrated with other lead-finding activities, Hing Sham of Elan said that he was neither pro-fragment nor anti-fragment – “it’s just another tool in the toolbox.”