Unknown knowns and binding kinetics

I hope that you all enjoyed the April Fool post but now it’s time to get back to business.  Before returning to Thermodynamics, I’d like to point you towards a couple of articles that you might find to be of interest.  In the first of these, Ben Davis and Practical Fragments’ Dan Erlanson take a look at some of what can go wrong when you screen fragments and it is noteworthy that they actively sought material from the fragment community before writing the review.  If you’re thinking about running a fragment screen, you do need to read this article which has already been featured in other blog posts ( 1 | 2 | 3).    

The article by Göran Dahl and Tomas Åkerud focuses on binding kinetics, specifically in the context of pharmacokinetics. In multistep processes, timescale determines relevance.  My take is that slow binding is equivalent to slow distribution and, at some point when the topic is raised, I will usually get round to asking whether slow distribution is something that you would want to design into a drug. The authors conclude that ‘the drug-target residence time appears to be limited in scope for prolonging duration of effect’ and the article provides a timely reminder that drugs act within a pharmacokinetic framework.

Literature cited

Davis & Erlanson (2013) Learning from our mistakes: The ‘unknown knowns’ in fragment screening. Bioorg Med Chem Lett In press DOI

Dahl & Åkerud (2013) Pharmacokinetics and the drug-target residence time concept. Drug Discov Today In press DOI

General FBDD Reviews: Pete's selections

There is plenty of review literature on FBDD and the following articles should provide a good introduction to the field.

Hesterkamp & Whittaker, Fragment-based activity space: Smaller is better. Curr. Opin. Chem. Biol. 2008, 12, 260-268. DOI

Congreve et al, Recent Developments in Fragment-Based Drug Discovery, J. Med. Chem. 2008, 51, 3661-3680 DOI

Hajduk & Greer, A decade of fragment-based drug design: strategic advances and lessons learned Nat. Rev. Drug Discov. 2007, 6, 211-219 DOI

Albert et al, An Integrated Approach to Fragment Based Lead Generation: Philosophy, Strategy and Case Studies from AstraZeneca's Drug Discovery Programs Curr. Top. Med. Chem. 2007, 7, 1600-1629 link

Erlanson et al, Fragment-Based Drug Discovery J. Med. Chem. 2004, 47, 3463-3482 DOI