Residence time

It would be a good idea for me to get back to blogging. I have been busy with a couple of conferences and grant writing, which explains my lack of attention to what’s cooking in the science universe.

One of the most memorable talks I heard at a recent CSC meeting held here in Toronto (I was in charge of the organic program, by the way) was that by Professor David Fairlie of The University of Queensland in Australia, an expert in drug design and a long time aficionado of cyclic peptides. As you might recall, cyclic peptides are often erroneously associated with pretty dreadful drug-like properties. Their oral bioavailability can be particularly dismal. The Fairlie paper says: “Who cares?”. Residence time is the main theme of the article. This parameter relates to the duration that a ligand is bound to its target. Fairlie considers his 3D53 molecule, which is a C5A antagonist, and reminds us that it is easy to fall prey to the assumption that IC50 (the concentration of an inhibitor where the binding is reduced by half) is the one and only “holy grail” when it comes to bioactive molecules. The reality is that IC50 is concentration dependent, which propels residence time to the foreground of Fairlie’s arguments. The paper nicely demonstrates that one might have a compound that is way inferior to its competitor when judged through in vitro biochemical binding assays, but jumps way ahead when evaluated in cellulo. In other words, a “lousy” molecule that is not too orally bioavailable and is not particularly potent, can stick to its receptor when it really matters and override potential shortcomings. Incidentally, this is one of the main reasons why there has been a lot of interest in reversible covalent inhibitors: they can drastically improve residence time. Another interesting fact about 3D53 is its synthesis, which I mentioned it in the past. It is a perfect reminder that there are remarkably well-behaved cyclizations that proceed on 100g-scale without the need for dilution.


4 thoughts on “Residence time

  1. It is also easy to fall prey to some of the propaganda concerning the benefits of slow binding kinetics. This propaganda typically touts the benefits of slow off-rate while ignoring the disadvantages of slow on-rate. Residence time tends to increase with affinity (the barrier for dissociation includes a ‘contribution’ from well depth) and, for given Kd, a slower off-rate comes with a slower on-rate. One needs to think about binding kinetics in the context of pharmacokinetics and a timescale for binding that is faster than that for distribution is not relevant to drug action. A slow on-rate means means that the drug engages the target to a lesser extent at peak concentration than would have been the case had the on-rate been higher. Slow binding to target can be seen as equivalent in vivo to slow distribution. Under what circumstances would you design a drug to distribute slowly?

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