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In Silico

Computational Nirvana

Wavefunction has a post about this paper from J. Med. Chem. on a series of possible antitrypanosomals from the Broad Institute’s compound collection. It’s a good illustration of the power of internal hydrogen bonds – in this case, one series of isomers can make the bond, but that ties up their polar groups, making them less soluble but more cell-permeable. The isomer that doesn’t form the internal H-bond is more polar and more soluble, but less able to get into cells. Edit – fixed this part.
So if your compound has too many polar functionalities, an internal hydrogen bond can be just the thing to bring on better activity, because it tones things down a bit. And there are always the conformational effects to keep in mind. Tying a molecule up like that is the same as any other ring-forming gambit in medicinal chemistry: death or glory. Rarely is a strong conformational restriction silent in the SAR – usually, you either hit the magic conformer, or you move it forever out of reach.
I particularly noticed Wavefunction’s line near the close of his post: “If nothing else they provide a few more valuable data points on the way to prediction nirvana.”. I know what he’s talking about, and I think he’s far from the only computational chemist with eschatological leanings. Eventually, you’d think, we’d understand enough about all the things we’re trying to model for the models to, well, work. And yes, I know that there are models that work right now, but you don’t know that they’re going to work until you’ve messed with them a while, and there are other models that don’t work but look equally plausible at first, etc., and very much etc. “Prediction nirvana” would be the state where you have an idea for a new structure, you enter it into your computational model, and it immediately tells you the right answer, every single time. In theory, I think this is a reachable state of affairs. In practice, it is not yet implemented.
And remember, people have spotted glows on that horizon before and proclaimed the imminent dawn. The late 1980s were such a time, but experiences like those tend to make people more reluctant to immanentize the eschaton, or at least not where anyone can hear. But we are learning more about enthalpic and entropic interactions, conformations, hydrogen bonds, nonpolar interactions, all those things that go into computational prediction of structure and binding interactions. And if we continue to learn more, as seems likely, won’t there come a point when we’ve learned what we need to know? If not true computational nirvana, then surely (shrink those epsilons and deltas) as arbitrarily close an approach as we like?

8 comments on “Computational Nirvana”

  1. Former MedChem says:

    I’ve witnessed this first hand. Inclusion of a piperidine ring formed a very stable six membered intramolecular h-bond with an amide NH. It was the difference if cell activity and no cell activity. Remove the N from the piperidine and the compound still had invitro enzyme activity but no cellular. I didn’t hypothesize that the cell activity was due to an intramolecular hbond until after the fact.
    I look at it as any desolation penalty given up by cell membrane diffusion is gained by the 4-5 kcals from the h bond. After it gets inside the intramolecular bond can be broken and re-solvated. Not quite the same as closing a ring with covalent bonds and hoping you have the right conformation: death or glory.

  2. Former MedChem says:

    In my last, the Nitrogen wasn’t “removed” but replace with a carbon.

  3. lt says:

    Another question would be if computational nirvana will be reached before or after nearly every target there is has already been drugged the hard way? And will it even matter post-Singularity? 😉

  4. Kevin Gaffney says:

    @Former MedChem
    Could you give us the reference or at least the Markush structure of this piperdine-amide moiety? Might help add to this knowledge base

  5. anon the II says:

    This is nice work. The reason it’s nice is that the authors use state of the art computational technology to address and try to understand a problem of tractable difficulty. But it is not a stepping stone to computational nirvana if that means larger systems like proteins. The problem is that the propagation of inherent error in force-field calculations will always limit their utility to simpler systems. The greatest advance of this work would be if more computational chemists spent time addressing tractable problems rather than working outside the bleeding edge of reality.

  6. Former Medchem says:

    #4. Picture a benzamide substituted at the 2-position with a piperidine. The N-H of the amide can form stable 6-membered intramolecular hbond ring with the N of pip. It was a head scratcher for a few days as to what was going on.

  7. Thanks for the plug Derek. Here’s another example – from the Jacobson group at UCSF – where six-membered hydrogen bonded rings between amide NH and heteroaromatic N groups of the kind noted by some of the commenters above are used to stabilize conformations and improve permeability.

  8. ankM says:

    Some time ago there was a nice review artice in J Med Chem from Roche about intramolecular hydrogen bonds. Everything was said there. Based upon this publication I checked our internal compound database to see if there is a general trend for intramolecular hydrogen bonds to improve physic-chemical parameters like solubility, permeability etc – there was not. As always the devil is in the detail. Therefore designing intramolecular HB to improve e.g. permeability is a valid design option which sometimes work – single success stories are expected, but are in some sense anecdotal (the success cannot be predicted).

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