Halogen Bonding

Investigators at Roche recently published a communication describing a systematic study of halogen bonding effects in protein-ligand complexes of human Cathepsin L (hCatL).  They found that an inhibitor incorporating a 4-chlorophenyl moiety enhanced binding affinity by a factor of 13, relative to the unsubstituted analogue, and x-ray cocrystal data suggested that the Cl atom made a favourable bonding interaction with a backbone CO group (see figure below).  This prompted them to prepare an array of analogues designed to explore this finding more comprehensively.

Binding mode of hCatL inhibitor with Cl bonding interaction highlighted

Whilst this type of protein-ligand interaction is not unprecedented the study the authors describe is the first of its kind to be reported in the literature (see note below) and makes for interesting reading.   The data they present, along with comparative calculated interaction energies,  argue that halogen bonds in protein-ligand complexes can contribute as much to binding affinity (and binding selectivity) as is the case for hydrogen bonds.  They demonstrate that the halogen bonds have strict geometrical requirements and that they increase in strength (all other factors being equal) with the mass of the halide substituent (Cl<Br<I) – with the exception of fluorides which are unable to interact in the same way.  They suggest, on the basis of their results, that establishing an ideal halogen bond might enhance protein-ligand affinity by as much as 74-fold (i.e. -ΔΔG = 2.6 kcal/mol) and that targeting such interactions to enhance protein-ligand binding affinity will increasingly find utility amongst medicinal chemists.

Calculated interaction energies for a model system

Note: A reader recently drew our attention to an earlier publication, from a Chinese group, in which they looked at a number of halogenated ligand-protein complexes and carried out single-point energy calculations to arrive at very similar conclusions to those outlined above.  They also highlighted the potential for using this type of interaction in drug design.

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12 Responses to Halogen Bonding

  1. Needle Finder says:

    Interesting article. I worked in a project, where an Iodine atom ineracted with the cabonyl group of Valine residue in the binding pocket and improved potency significantly. All the attemps to replace Iodine while maintaining potency failed.

    • Anonymous says:

      this phenomena is very known for years …
      there many article about it,
      even though it is known in poor chinese population…

      • mcb says:

        Thanks for your comment and for the link. That’s also a very nice paper which I wasn’t aware of and it wasn’t referenced in the Roche paper. Whilst the phenomenon, as you point out, is well known (and this was alluded to in the post) I guess the study in the Roche paper is the first such systematic study reported (i.e. an SAR investigation within one protein complex). However the paper you referenced does precede it in arriving at many of the same conclusions so thanks for bringing that to our attention. I’ve added a note to the post and have linked to the paper directly. I’m sure our readers will find it interesting.

  2. mcb says:

    Apologies for the late reply. Thanks for sharing that. What did you do in light of this finding? Carry on with the iodine in place or move away from the series?

  3. milkshake says:

    I wonder if the aryl iodide in such place can be replaced with 3-subst thiophene, or with a benzothiazole, etc. Sulfur containing heteroaromatics with 5-membered ring carry a partial positive charge on sulfur atom, and if there is a carbonyl group nearby the electrostatic effects orient it quite reliably so that the oxygen in CO is pointing towards S. This has been for example documented Dasatinib. There are similar interactons between S atom and pyridine/pyrimidine ring N

  4. mcb says:

    Interesting idea milkshake. Do you have a handy reference for the Dasatinib example you mentioned? Certainly an idea worth exploring in this situation. Hopefully Needle Finder will let us know whether they tried that.

  5. milkshake says:

    I don’t have a reference at hand, I know this because I have been working on series of Dasatinib analogs about 5 years ago and my boss had pointed to me this hetaryl S …O=C interaction that shows quite prominently in the crystal structure. Apparently it is a quite general phenomena seen in other kinase inhibitors too. I remember Curious Wavefunction wrote post about this also, about 2 years ago.

  6. milkshake says:

    It was also mentioned at Kinase Pro few years back, here is the link:

  7. mcb says:

    Thanks milkshake. Very interesting link. Now all we need is for someone to try this out…

  8. milkshake says:

    That would be easy enough. Should I send you my resume?… (My gmail address is attached).

  9. Needle Finder says:

    Hi MCB, We progressed the molecule with iodine group into phase I, after establishing its stability under a variety of stress conditions including photostability studies.

    We tried diffrent functional groups to replace iodine, but did not try the options suggested by Milkshake

  10. mcb says:

    Thanks Needle Finder. That’s interesting. I would guess that not that many iodides have been progressed to the clinic.

    Tomas, I sent you an e-mail.

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