Journal of Computer-Aided Molecular Design 2011 Special FBDD Issue

The most recent issue of J. Comput. Aided Mol. Des. is entirely devoted to fragment-based drug discovery. This is the second special issue they’ve dedicated to this topic, the first one being in 2009.

Associate Editor Wendy Warr starts by interviewing Sandy Farmer of Boehringer Ingelheim. There are many insights and tips here, and I strongly recommend it for a view of how fragment-based approaches are practiced at one large company. A few quotes give a sense of the flavor.

On corporate environment:

In most cases, the difference between success and failure has little to do with the process and supporting technologies (they work!), but rather much more to do with the organizational structure to support FBDD and the organizational mindset to accept the different risk profile and resource model behind FBDD.

On success rates:

We have found that FBDD has truly failed in only 2-3 targets out of over a dozen or so.

On cost:

FBDD must be viewed as an investment opportunity, not a manufacturing process. And the business decisions surrounding FBDD should factor that in. FBDD is more about the opportunity cost (of not doing it) than the “run” cost (of doing it).

On expertise:

Successful FBDD still requires a strong gut feeling.

On small companies:

In the end, FBDD will always have a lower barrier to entry than HTS for a small company wanting to get into the drug-discovery space.

The key to success for such companies is to identify or construct some technology platform.

There’s a lot of other really great content in the issue, much of which has been covered in previous posts on fragment library design, biolayer interferometry, LLEAT, and companies doing FBLD. The other articles are described briefly below.

Jean-Louis Reymond and colleagues have two articles for mining chemical structures, one analyzing their enumerated set of all compounds having up to 13 heavy atoms (GDB-13), the other focused on visualizing chemical space covered by molecules in PubChem. They have also put up a free web-based search tool (available here) for mining these databases.

Roland Bürli and colleagues at BioFocus describe their fragment library and its application to discover fragment hits against the kinase p38alpha. A range of techniques are used, with reasonably good correlation between them.

Finally, M. Catherine Johnson and colleagues present work they did at Pfizer on the anticancer target PDK1 (see here and here for other fragment-based approaches to this kinase). NMR screening provided a number of different fragment hits that were used to mine the corporate compound collection for more potent analogs, and crystallography-guided parallel chemistry ultimately led to low micromolar inhibitors.

Journal of Computer-Aided Molecular Design Special FBDD Issue

Our friends over at FBDD-Literature have already highlighted this, but it bears repeating that the entire August issue of J. Comp. Aid. Mol. Des. is devoted to FBDD. For aficionados of all things silicon, there are articles on computational chemistry applied to FBDD generally as well as on more specific topics such as MCSS, NovoBench, FTMap, and two papers on Glide (here and here).

But don’t be put off by the name of the journal: with 14 articles covering close to 200 pages, there is something here for almost everyone, even for those whose interest in computers ends at using them to read this blog! A brief editorial outlines the challenges of FBDD, and a longer introductory piece gives an overview of the field. Several articles focus largely on specific targets such as p38alpha, heparanase, and Eg5, while one is devoted to assessing druggability.

Finally, two articles address the important topic of designing fragment libraries, one from the perspective of big pharma (nicely summarized here), the other from biotech.