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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 17, 2013

Halogen Bonds

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Posted by Derek

Here's a recent paper in J. Med. Chem. on halogen bonding in medicinal chemistry. I find the topic interesting, because it's an effect that certainly appears to be real, but is rarely (if ever) exploited in any kind of systematic way.

Halogens, especially the lighter fluorine and chlorine, are widely used substituents in medicinal chemistry. Until recently, they were merely perceived as hydrophobic moieties and Lewis bases in accordance with their electronegativities. Much in contrast to this perception, compounds containing chlorine, bromine, or iodine can also form directed close contacts of the type R–X···Y–R′, where the halogen X acts as a Lewis acid and Y can be any electron donor moiety. . .

What seems to be happening is that the electron density around the halogen atom is not as smooth as most of us picture it. You'd imagine a solid cloud of electrons around the bromine atom of a bromoaromatic, but in reality, there seems to be a region of slight positivecharge (the "sigma hole") out on the far end. (As a side effect, this give you more of a circular stripe of negative charge as well). Both these effects have been observed experimentally.

Now, you're not going to see this with fluorine; that one is more like most of us picture it (and to be honest, fluorine's weird enough already). But as you get heavier, things become more pronounced. That gives me (and probably a lot of you) an uneasy feeling, because traditionally we've been leery of putting the heavier halogens into our molecules. "Too much weight and too much hydrophobicity for too little payback" has been the usual thinking, and often that's true. But it seems that these substituents can actually earn out their advance in some cases, and we should be ready to exploit those, because we need all the help we can get.

Interestingly, you can increase the effect by adding more fluorines to the haloaromatic, which emphasizes the sigma hole. So you have that option, or you can take a deep breath, close your eyes, and consider. . .iodos:

Interestingly, the introduction of two fluorines into a chlorobenzene scaffold makes the halogen bond strength comparable to that of unsubstituted bromobenzene, and 1,3-difluoro-5-bromobenzene and unsubstituted iodobenzene also have a comparable halogen bond strength. While bromo and chloro groups are widely employed substituents in current medicinal chemistry, iodo groups are often perceived as problematic. Substituting an iodoarene core by a substituted bromoarene scaffold might therefore be a feasible strategy to retain affinity by tuning the Br···LB (Lewis base) halogen bond to similar levels as the original I···LB halogen bond.

As someone who values ligand efficiency, the idea of putting in an iodine gives me the shivers. A fluoro-bromo combo doesn't seem much more attractive, although almost anything looks good compared to a single atom that adds 127 mass units at a single whack. But I might have to learn to love one someday.

The paper includes a number of examples of groups that seem to be capable of interacting with halogens, and some specific success stories from recent literature. It's probably worth thinking about these things similarly to the way we think about hydrogen bonds - valuable, but hard to obtain on purpose. They're both directional, and trying to pick up either one can cause more harm than good if you miss. But keep an eye out for something in your binding site that might like a bit of positive charge poking at it. Because I can bet that you never thought to address it with a bromine atom!

Update: in the spirit of scientific inquiry, I've just sent in an iodo intermediate from my current work for testing in the primary assay. It's not something I would have considered doing otherwise, but if anyone gives me any grief, I'll tell them that it's 2013 already and I'm following the latest trends in medicinal chemistry.

Comments (16) + TrackBacks (0) | Category: Chemical Biology | Chemical News | In Silico


COMMENTS

1. Carl Feynman on January 17, 2013 12:43 PM writes...

You need to close the first quotation tag.

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2. Derek Lowe on January 17, 2013 12:51 PM writes...

Ack, so I do. Just fixed it; that's what I get for eating a sandwich at the same time I'm typing the blog entry, I guess.

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3. Frank Dean on January 17, 2013 1:02 PM writes...

Interesting that the thyroid hormones T3 and T4 have 3 and 4 iodines, respectively.

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4. Pete on January 17, 2013 1:03 PM writes...

Halogen bonding has been with us for long time.

‘In 1839 Bouchardat, a medical writer in Paris, recounts that, when dogs were being surreptitiously poisoned with strychnine in Paris, and an antidote was asked for, first Guibourt recommended powdered galls, and then Donné asked for iodine tincture, whereupon Bouchardat himself, approving the use of iodine, said that they should use it in potassium iodide solution.’

A.B. Prescott The Periodides, JACS, 1895, 17, 775-781.

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5. a. nonymaus on January 17, 2013 1:39 PM writes...

This phenomenon could be very important in ligand-receptor docking, e.g. the CNS drugs DOB and DOI. Is it included in any of the molecular modeling force-fields that computational folks typically use for that?

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6. Pete on January 17, 2013 2:14 PM writes...

Force fields typically struggle with halogen bonding since they normally use atom-centered charges and the electronegativity of halogens ensures that these are negative. I seem to recall one of the software companies (possibly Schroedinger?)looking into this. I've not seen much in the literature on halogen bonding to solvent water.

You can see similar effects with sulfur and a large potency difference between SCF3 and OCF3 substituents could be diagnostic of an interaction between the sulfur and a hydrogen bond acceptor.

I don't see anything wrong with testing the iodo intermediate. The thing to watch is whether you lose more in solubility than you gain in potency (solubility substituent 'constants' are available from matched molecular pair analysis). Also if your crystallographers can't see it you know it's time to get new crystallographers. I believe that there are some concerns about iodo substituents being oxidised althougfh this is not something I know a whole lot about.

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7. Toad on January 17, 2013 2:36 PM writes...

A question is why you would not routinely submit your intermediates for assaying, or for use in HTS screens later. Is this not something from which most companies have benefited?

Personally, I have seen major advances and whole programs change on unexpected data on purified intermediates.

I know you can't respond to this directly, but I am curious if this is or is not a routine practice in both small and large companies.

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8. Christophe Verlinde on January 17, 2013 3:02 PM writes...

Here's a very recent attempt to incorporate sigma holes in force-fields:
Megan Carter, Anthony K. Rappe, and P. Shing Ho.
Scalable Anisotropic Shape and Electrostatic Models
for Biological Bromine Halogen Bonds.
J. Chem. Theory Comput., 2012, 8 (7), pp 2461–2473
DOI: 10.1021/ct3001969

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9. John Wayne on January 17, 2013 3:21 PM writes...

@7: I agree that submitting clean intermediates is a great practice, and I have seen similar positive outcomes on projects.

Based on the experiences of both colleagues and I, companies have a diversity of policies on the subject. I've seen and heard of everything from 'Chemist Bob doesn't bother submitting his intermediates' to 'Chemist Jack is just trying to look more productive and is wasting company resources.' Culture is everything.

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10. Boghog on January 17, 2013 3:57 PM writes...

@3: Frank Dean
> "Interesting that the thyroid hormones T3 and T4 have 3 and 4 iodines, respectively."

And even more interesting that one of the iodine atoms of T3 forms a halogen bond with a backbone carbonyl group in the thyroid hormone receptor (see for example PDB 2H77, 3.1 Ã… distance between the backbone carbonyl group of Phe218 and a T3 iodine atom).

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11. Chemist For Life on January 17, 2013 6:30 PM writes...

One interesting side point regarding this paper are the amazingly beautiful illustrations and figures the authors included. Crisp, clear, and colorful - it's like watching the Food Network in HD!!

They win the prize for most aesthetically pleasing article 2012. Well done Wilcken et al.

Oh, and by the way an interesting article to boot!

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12. Patrick Lam on January 17, 2013 7:44 PM writes...

The first rational use of halogen bonding in SBDD was done in 1996. (238th ACS national meeting, Washington DC. Org Div abs. 58, Aug 16, 2009.):
"...In 1996, inspired by Lommerse’s observation of novel halogen bonding in the crystal packing of dichloroquinone (JACS, 3108,1996), we successfully utilized the electro-positive tip of halogen to replace amidine to interact with the conserved electro-negative asp 189 of Factor Xa. A crystal structure of FXa/inhibitor was subsequently obtained to prove the existence of halogen bonding (observed I-O distance is 3.2Å; normal VDW contact distance is 3.5Å). To the best of our knowledge, this is the first successful utilization of halogen bonding in rational drug design...."

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13. Anonymous on January 18, 2013 4:44 AM writes...

#6Pete "Also if your crystallographers can't see it you know it's time to get new crystallographers."

Don't be so cocky. It is called radiation damage and heavy halogens are especially susceptible. Not much can be done in many cases unless go back in time and do collection on low energy sources instead of synchrotron.

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14. Teddy Z on January 18, 2013 8:19 AM writes...

I think you are thinking about Ligand Efficiency incorrectly. Here is a rant from a former CC colleague of mine. http://practicalfragments.blogspot.com/2012/05/why-not-amw.html
LE should be based on heavy atom count, not MW. So, for me, iodine vs. Br, Cl, F is not a big deal from an efficiency standpoint.

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15. Derek Lowe on January 18, 2013 9:09 AM writes...

#14 Teddy Z:

That's been an arguing point around my company as well, and deserves its own post here. Coming up soon!

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16. LJStewartTweet on January 19, 2013 1:04 PM writes...

Great points #14 and Derek #15. Derek. Great to hear you nominating an iodo containing molecule.

For those of you interested in looking closer at where Iodo can sit in proteins. You can run a PDB check to find all the structures that contain I atoms. Many of them are from SSGCID.org

You may know that we use Iodo in SAD phasing at SSGCID extensively and have published on interesting positions that we see Iodo finding a home in protein structures ! Don't be afraid of Iodo, it can be your friend.

http://www.ncbi.nlm.nih.gov/pubmed/21359836
J Struct Funct Genomics. 2011 Jul;12(2):83-95. doi: 10.1007/s10969-011-9101-7. Epub 2011 Feb 27.
SAD phasing using iodide ions in a high-throughput structural genomics environment.

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