Here’s a ten-year look back at the whole concept of residence times in drug discovery, published by Bob Copeland of Epizyme in Nature Reviews Drug Discovery. He’s the one to write it, since he’s one of the key developers of the whole concept, which certainly seems to have made a home for itself in the way that we think about our compounds’ activity.
What it all comes down to is looking at on-rates and off-rates for drugs binding to their targets. (The off-rates vary much more widely than the on-rates, most of the time). The renewed attention to this kinetic behavior fit perfectly with the wider adoption of surface plasmon resonance (SPR) assays, which give you detailed information on both steps for everything you put into them (well, everything that actually works, but you know what I mean). Maximizing your compounds’ residence times, which in practice usually means reducing off-rates, can be a powerful way to think about optimizing drug candidates. That has you improving both potency and pharmacokinetics at the same time, rather than thinking about them as separate problems.
The advent of SPR and other newer biophysical methods has also made it more feasible to get the details on just what actually happens when a compound binds. The more potent a ligand is, the more likely it is to work its way in through a rather complex series of steps – what’s traditionally been called the “induced fit” model, where both the compound and the binding site are adjusting to each other. This is why the old intro-to-biochemistry “lock and key” metaphor can only take you so far. If both lock and key were both mode of some sort of fairly stiff jelly and came to grips with each other in a series of shifts and rearrangements, that would be a more accurate mental picture. The further and more thoroughly a compound works itself into a binding site, the more steps there probably are that have to be reversed to get back out – potency and residence time are thus usually correlated. Maybe we should switch over from locks and keys to trucks backing into tricky loading docks.
You can get into some interesting situations if the residence time is longer than the pharmacokinetic half-life, such as having a drug that continues to work after it should already be gone from the system. In some cases, the limits on its activity are imposed by the half-life of its protein target – how long does a given protein molecule last in the cell before being turned over? These thoughts often come up when discussing covalent compounds (which bind irreversibly to their targets), but it’s important not to put these in some sort of separate mental category. They’re just the far end of the residence-time continuum, out there on the asymptote. You can see these things with noncovalent compounds, too – in the end, what’s important is the residence time itself, not necessarily whether or not a bond has been formed in order to increase it. Here’s a paper on BTK inhibitors that addresses just this point.
That reference (and many other recent ones) are to be found in the NRDD article, making it an excellent opportunity to get caught up on work in the field. Definitely recommended!