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Analytical Chemistry

Only Connect

Anyone who’s done fragment-based drug design (especially) or who has just looked at a lot of X-ray crystal structures of bound ligands will be able to back up this statement: if you sit down with a series of such structures, all bound to the same site, it is very, very difficult to rank-order them in terms of their actual binding constants against that site. The gross features can help you out – if there are like three obvious hydrogen bonds, sure, that’s a tip-off that your ligand has found a good home versus one that’s just sort of floating in there.

But rarely do we get anything so clear-cut to work with. For the most part, you have a set of hydrophobic interactions, pi-cloud interactions, some polarities pointing vaguely toward some opposite polarities, a bit more occupancy here and a bit less here, differently displaced water molecules, and so on. Evaluating these and adding them up is the very opposite of straightforward. It’s not at all easy to judge the strength of such binding events, and it’s even harder to judge what energetic price was paid to get to them. Changes in the solvation of the ligand, of the protein, changes in its conformation, the balance of entropy and enthalpy in all of these – no, that ain’t trivial, which is why we have such a hard time modeling all this, despite billion-dollar incentives to figure out how.

Here’s a new paper that shows that we really don’t even have the full list of such interactions sorted out yet. The authors (from Roche and the Cambridge Crystallographic Data Center) have gone back through that database looking for lesser-known “nonclassical” interactions. They’re especially focusing on aryl halogen atoms, on nitriles, sulfonyl groups, and sulfur atoms inside aromatic rings. This sort of search has certainly been done before, but this time a new approach to the statistics has been used, to try to account for directionality and normalizing for frequency of occurrence. There are an awful lot of data points in the PDB, and a lot of ways to slice them up (and it should always be kept in mind that some percentage of the PDB structures are wrong, subtly or not-so-subtly, especially in the small-molecule ligands.

But what this paper finds is evidence for the “sigma-hole” halogen-carbonyl interaction (for chlorine and higher), aryl fluorine interactions with the carbon of both carbonyl and guanidine groups (Arg side chains), nitrile with the terminal nitrogens of those Arg guanidines and with the NH of indoles (Trp side chains), sulfonyl oxygens with NH amide backbones, and many more. These are presented, usefully, as whether they occur at greater or less than rates expected by chance. On the other hand, there’s no particular evidence for a number of other interactions that are at least hand-wavingly plausible, such as NH hydrogen bond donors with fluorine as acceptor (at rates greater than chance), and many that come in at significantly worse than chance and are thus clearly unfavorable (such as aryl Cl with donor sulfur atoms).

Both sets (significantly greater than chance and significantly worse) are quite useful, and should help to refine structure-based drug design ideas and virtual screening efforts. The paper, as you’d expect, has details of the preferred (and non-preferred) geometries for all of these interactions, as extracted from the data, and I’d definitely recommend it to computational ligand-fitters of all persuasions. The authors state that they’re continuing to dig for more interactions, and also mention that a focus on the unfavorable ones is warranted, and I’d agree. Our human bias is to pay attention to favorable “winning” cases, but you’d also very much want to know what to avoid – or more precisely, what your molecules and proteins are going to avoid whether you know it or not!

12 comments on “Only Connect”

  1. anon says:

    A basic question. What causes the “sigma-hole”?

    1. antiaromatic says:

      It’s an n->pi* interaction from lone pairs on the halogen to the pi* on the carbonyl. If you’re more interested in this type of interaction, see the work of Ron Raines on the topic. In many cases can be a dominating inter and intramolecular interaction that dictates conformation.

      1. MDB says:

        This is not correct; backwards, in fact, with respect to the direction of electron “flow”. The sigma hole, in the context of the paper Derek highlights (and that of those who coined the term) describes a region of relative positive electrostatic potential on a halogen in molecule R-X, opposite but collinear with respect to the R-X sigma bond. This so-called sigma hole may interact in productive fashion with electron-rich agents such as lone pairs on nitrogen, oxygen, etc. Refer to the key literature of Clark, Politzer, and Murray for more detail on the topic.

  2. HA Lurker says:

    Typo that confused me for a sec:
    whether they occur at greater or less *than rates

  3. Wavefunction says:

    “NH hydrogen bond donors with fluorine as acceptor (at rates greater than chance)”

    Another strike against fluorine as hydrogen bond acceptor, first comprehensively pointed out by the great Jack Dunitz in the 90s who analyzed thousands of crystal structures and found half a dozen in which fluorine could *perhaps* serve as a HB acceptor. The short answer is that it really likes to hold on to its electrons.

  4. A Nonny Mouse says:

    The television programme is much more fun (one for the British audience).

  5. Barry says:

    That “sigma hole” sounds like someone has just rediscovered what Jack Dunitz did in the 80s, tabulating and evaluating diffraction structures for (productive) interactions of lone-pairs w/ carbonyls.

    When trying to design ligands by linking up these fragment contributions, we also need to know the tolerances of each. Hydrogen-bonds are notoriously directional (likewise the “Dunitz angle” for donation to a carbonyl). Within the tool-kit of covalent bonds, it is often impossible to satisfy the fussy angular requirements of two or three or four sub-sites at once.

    1. Jed Burns says:

      As MDB explained so elegantly, Halogen bonding is due to the “sigma hole”, a n -> sigma* from a carbonyl lone pair (though it is not limited to carbonyls) to the halogen antibond and not(!) the other way around (halogen n -> pi* carbonyl). They have a pretty notable presence in MOF community. More props to MDB: the Politzer, Murray and Clark review is Phys. Chem. Chem. Phys., 2010,12, 7748-7757.

      It’s intuitive to compare it to electrophilic halogenating agents (where nobody gets too concerned with a nucleophile attacking a halogen) – the strength of halogen bonds correlates with the how electron withdrawn the alkyl/aryl halide is. Or something like a bigger, uglier hydrogen bond 😉

      Derek, how bout some links? There appears to be some confusion.

  6. Grad student says:

    Interesting that fluorine as H-bond acceptor doesn’t register high on the likelihood scale. It wasn’t in the context of a ligand & binding pocket, but I definitely made some compounds in a methodology project that seemed to show F-H-O bonding (H shift ~14.4 ppm, sharp singlet) in a fused-bicyclic system of peri-sub’d fluoro/hydroxyl groups. It seems physically/chemically possible, if perhaps not as much in a more “lifelike” system as a ligand/enzyme pocket?

    1. Once upon a time a grad student says:

      In what solvent? A weak attraction at low dielectric is easily overcome by a stronger attraction to water, or indeed trying to find anything else but OH…F, in a mixed environment.

  7. Barry says:

    14.4ppm sounds huge. You saw the 1H resonance shifted downfield because the Fluorine was donating electron density. That’s paradoxical at least.

  8. cadd says:

    Hmm. I’m sure that an almost infinite number of currently unappreciated but favorable interactions exist, but I’m not convinced that knowing about these is going to transform anyone’s drug discovery effort. By definition, if these interactions were strong then they wouldn’t be uncommon.

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