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Fun With Thermodynamics

Here’s a very good review in J. Med. Chem. on thermodynamics and drug discovery. That topic has come up at this site several times over the years, and I’ve been wondering if anyone’s reached a consensus yet. What I take away from this new article is “Nope. Not yet.” Update: see also this review, also from earlier this year.
The hope, fanned by the work of Ernesto Friere and others, has been that there would be some sort of thermodynamic signature of compound binding that would help pick better compound series to work on. That’s easier said than done. For one thing, you have to be able to do good calorimetry on your binding target, which isn’t always possible. But even if you have plenty of protein and have the system well worked out, there are complications, and that’s what this new article goes into.
Wavefunction has a good post on those, in response to this same article. One problem has been that we medicinal chemists have tried to oversimplify things, to work down to rules of thumb, and I don’t think that ligand binding is amenable to that sort of thing. (Most of the really important topics in drug discovery – think toxicology – aren’t reducible in that way, either, as it turns out). There is no useful textbook titled “Thermodynamics: A Hand-Waving Approach”, unfortunately, because that approach doesn’t work so well.
The hand-waving rules, in this case, have been “Pick the enthalpic-driven compounds”, “Displace water molecules to pick up favorable entropy”, among others. But there are too many exceptions. I gave a talk on entropic factors here at my workplace a few years ago, and as I dug into the topic, I found that water molecules could (and have been) assigned to every category possible, which is what everyone who takes a close look at the field discovers. Sometimes, indeed, you can displace one, and it goes flying off into entropic heaven and gives you a better T-delta-S term. But sometimes you displace one and it ends up more ordered out there in solution than it was in the protein binding site, which is counterintuitive. And sometimes (probably more often) it’s the enthalpic effects of its hydrogen bonding, on both the protein and out in the bulk phase, that really determine the energetics. Thinking that displacing a water is always a good thing is just too reductionist, because the self-evident truth about water molecules is that they are not all created equal.
This is only the beginning of the complications. As the paper illustrates, in detail, similar ligands in the same SAR series (to the eyes of a medicinal chemist) can work through very different sorts of thermodynamics. Networks of water molecules, subtle effects on protein structure and stabilization, variable hydrogen-bonding networks, entropic and enthalpic penalties or bonuses from the bulk solvent, the localized water molecules, the ligand molecule, and the protein itself are all in play. You can’t generalize – that’s the message.
No one particularly likes to hear this. As scientists, we want to generalize, to discover trends and rules that we can use to cover more ground more quickly. As employees in hierarchical organizations, many of us would like to be able to report that we have found such things, through our own valuable keenness, and are now exploiting them (and deserve to be gainfully employed for doing so). “We’ve got a handle on this” is what we’d like to tell ourselves and to tell others. But when it comes to the thermodynamics of ligand binding, no, I don’t think we have a handle on it yet. There may be rules and trends that will help us out, but they’re not going to be as broadly applicable and wide-ranging as we’d once hoped.

14 comments on “Fun With Thermodynamics”

  1. Some idiot says:

    Nice piece… I always hop into this sort of thing thinking “Yes, we should be able to do this thermodynamically in a sensible way”, and then after a bit more thought thinking “no, we can’t, because there is far too much “on a knife’s edge” complexity, which we have no earthly chance of being able to handle in a sensible way. At the moment. But I still have the hope that we will be able to handle it at some stage (mind you, I will not even try to guess which year/decade/century this will be…
    But I love this stuff, as it teaches us (or should, at least, in my opinion) that the world out there is complex and beautiful, and every now and again through the haze and noise we get a glimpse of just how beautiful it is… Now, if only we could get some better treatments out of it….! But at any rate I will always love the view…
    (-;
    Incidentally, Derek, a bit of extra entropy got into your piece, with an itallics that wasn’t clsoed, with the result that it has flowed down the page… (on a side point, is that more entropy or less? Probably actulally slightly less… maybe…)

  2. I can see through the dead wood says:

    It’s amazing how much time is wasted at AZ just writing up reviews. Perhaps their mission should be more dedicated toward drug discovery than trying to find the next topic for the next review.

  3. Not an AZ employee says:

    #2: Another way to look at it is to say that AZ is at least making a useful intellectual contribution to drug discovery by writing these thoughtful reviews (and there have been more than a few from them). Is any other company doing even that?

  4. cc says:

    The complexity of interpreting thermodynamic data is tightly related to the difficulty of molecular modeling; we don’t fully understand non-covalent interactions, we don’t understand water and we certainly don’t understand entropy

  5. Provocateur says:

    Thermodynamics and kinetics are always ‘,after the fact’ done items to justify the narrative.I sod like to know where it has been useful in drug discovery.

  6. Christophe Verlinde says:

    Another splendid review on the intricacies of thermodynamics of ligand binding appeared earlier this year by Gerhard Klebe:
    Nature Reviews Drug Discovery 14, 95–110 (2015) doi:10.1038/nrd4486
    “Applying thermodynamic profiling in lead finding and optimization”

  7. TX raven says:

    I thank the AZ folks for the many reviews they have written.
    Always thought-provoking.
    Keeping things much more interesting than “lower the cLogP” view of med chem, so prevailing these days.

  8. ed says:

    yes #3, useful contribution, hidden behind Nature pay-wall!
    So in effect AZ scientist time spent making Nature Group money.

  9. Wavefunction says:

    Thanks for the plug, Derek. #8: The content is actually freely available if you create an account on the site.

  10. CS says:

    And since biological systems are highly dynamic and operating a very long way from equilibrium, the thermodynamics of a particular binding event are probably irrelevant anyway.

  11. Pete says:

    When trying to interpret enthalpy and entropy changes associated with binding it is important to remember that the contribution of an intermolecular contact (or group of contacts) to affinity is not, in general, an experimental observable. It should also be pointed out that free energies calculated from simulations are usually obtained directly (as opposed to calculating enthalpy and entropy separately). The contact between polar and non-polar surface is not inherently repulsive even though we believe that it destabilizes the protein-ligand complex.

  12. An AZ employee says:

    #2 To be fair, this is actually a piece of work that contains some new experimental data, thus it’s not just a review.
    #5 I guess, even though kinetics and thermodynamics are intimately linked, they measure different consequences of ligand binding. Thus, I would not try to make this more general statement, as there are better chances for kinetic data to be used during decision making in drug discovery (e.g. increasing the one rate to tackle PPIs more effectively).
    #6 I guess this review comes to a somewhat different conclusion.

  13. Ed says:

    #5 true. But if you do have good PK/PD models you might find that case were you need fast on-rate OR slow off-rate. However, in most cases you need both..:)

  14. Wlm says:

    ‘There is no useful textbook titled “Thermodynamics: A Hand-Waving Approach”‘
    But there is! There’s also “Cancer Genomics: A Hand-Waving Approach”, “Medical Genetics: A Hand-Waving Approach”, “Post-Humanism: A Hand-Waving Approach”, and finally, “How Big Data Makes Your Life Better: A Hand-Waving Approach”. I think they’re all available from Singularity University Press.

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