Fragments vs Pharma

As the year winds down I’ve been catching up on some reading, and finally got to the study that Paul Leeson and Stephen St-Gallay published a couple months ago in Nature Reviews Drug Discovery. They analyzed compounds disclosed in patent applications from 18 large companies (mostly pharmaceutical companies, but also Amgen and Vertex) between 2000 and 2010. Even controlling for different targets, the companies differed considerably in the drug-likeness of their compounds, with some companies producing compounds that are considerably larger and more lipophilic than other companies. In the Pipeline has an excellent summary of the paper overall.

But what caught my eye as being of special interest to readers here is a small part of the main paper. In addition to analyzing large companies, Leeson and St-Gallay dug into the patent applications of a fragment-focused company, Astex Therapeutics (now Astex Pharmaceuticals). A dozen of the kinase targets pursued by Astex were also pursued by one or more of the large companies, and by analyzing the inhibitors from each organization, the authors could compare leads derived from fragments with leads derived using conventional approaches. The results were striking:

With the exception of chirality and sp³ measures, molecular properties are more drug-like in the compounds patented by Astex Therapeutics. This specific application of fragment-based drug design is perhaps the most compelling realization to date of the principle of lead-like chemical starting points that was first proposed more than a decade ago.

This does not mean that FBDD is a panacea: as noted previously, it is all too easy to take a perfectly good fragment and turn it into an obese grease-ball. But an attractive fragment, combined with adept medicinal chemistry and intolerance for unnecessary lipophilicity, can be a powerful combination.

And with that, Practical Fragments says goodbye to 2011. Thanks to all of you for reading, and special thanks for posting comments. May you all have a happy and successful 2012!