In drug discovery, there is a long history (for example, see 1 and 2) of associating structural changes with quantitative changes in activity. We were interested to read that a hydrogen bond between a neutral donor and neutral acceptor will contribute no more than a factor of 15-fold to binding affinity.
This is really interesting. Those of you who read the kinasepro column, will know that the IP situation in the kinase area is challenging because of the huge number of patents. You'll also know that many kinase inhibitors interact with the hinge region through neutral-neutral hydrogen bonds. Now that quoted 15-fold figure actually represents an upper limit. So there you have it, dump the hydrogen bond and think of all the brand new, bright and shiny chemical space you can have all to yourself if you just think outside the box. And don't forget to check Carbon-Based Curiosities if bright and shiny is your sort of thing.
Now before you bet your project (and maybe even your company) on the the magic 15-fold upper limit, should we perhaps take a closer look at where this figure comes from? How much data is it based on and what are the relevant reference states? We will attempt to answer these questions in a short series of Crapshoots. Until then, all that needs to be said is Happy Christmas from The Crapshoot, The Blue Team and the Red Team.
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2 comments:
It would be great if you also touch on the hydrophobic enclosure hypothesis, which seems to make some intuitive sense doi: 10.1073/pnas.0610202104
In the case of kinases, the structures of some apo forms indicate that water molecules are often interacting with the hinge atoms whilst being "sandwiched" above and below the plane by hydrophobic residues.
It should be possible to take a look at hydrophobic interactions in this series of Crapshoots although this will be after the contribution of hydrogen bonds has reviewed. Hydrophobic enclosure will lead to stronger hydrophobic interactions and, where they can form with appropriate geometry, stronger hydrogen bonds between protein and ligand. Stay tuned.
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