Cl - - - - O « KinasePro

Cl - - - - O

October 18, 2007 by kinasepro

I am somewhere between faithless and agnostic on the role of through space ‘halogon bonding’, but earlier a reader pointed us towards a review on the subject from within the recent kinase-thematic issue of Current Topics in Medicinal Chemistry.

With this as a backdrop, here’s another very interesting structure from SGC: 2VAG is Clk1 bound to a dichloroindole. If it is indeed as potent as has been suggested to me, then I might be moving towards believer status.

$O=C(C(N2C)=C(/C(C#N)=C\N)C1=C2C(Cl)=C(Cl)C=C1)OCC$

The animation shows their earlier 1z57 with Hymenialdisine, a somewhat more traditional kinase inhibitor.

Posted in General Interest | 20 Comments

20 Responses to “Cl - - - - O”

on October 19, 2007 at 11:22 am1 Wavefunction

I would also like to point to one of the early PNAS reviews:
PNAS | November 30, 2004 | vol. 101 | no. 48 | 16789-16794
The ESP surfaces are pretty suggestive.
Cool pic switching by the way.
on October 19, 2007 at 12:16 pm2 braf.v600e

You better believe, halogens have been responsible for some intriguing SAR. It would be very interesting to see some of the SAR around this molecule.
…I wonder if that sort of study is within the SGC mandate…
on October 19, 2007 at 5:55 pm3 Chris

How did you generate the image? I’ve been debating whether to start using Jmol but my javascript is very rusty.
on October 19, 2007 at 9:04 pm4 kinasepro

I use pymol, photoshop, and chemdraw to generate all the images around here.
on October 20, 2007 at 8:43 am5 rookie

How does the CL—O interaction happen as that
of N-H—-O? Any expert can explain it?
on October 20, 2007 at 8:49 am6 rookie

But I like this pic althrou its hard to beleive. Where are millshake ( I enjoyed his/her insights on medicinal chemistry very much) and other guys who liked to make bloggy ‘noise’?
on October 20, 2007 at 4:11 pm7 braf.v600e

ImageJ is a good open source alternative to photoshop:

http://rsb.info.nih.gov/ij/
on October 20, 2007 at 9:47 pm8 milkshake

I have seen SAR examples where Cl on benzene ring was replaceable with OMe without much loss in potency - but not with methyl. (even though methyl is close in size to Cl than OMe is)

Also, it is my impression that X-ray based discussion of interactions is mostly qualitative - when you see a contact between the ligand and protein you don’t allways know how much binding energy this interaction is actually contributing - and more subtle effects, especially electronical ones are hard to notice from X-ray even as they can have huge effect on potency.
on October 20, 2007 at 10:22 pm9 kinasepro

bloggy noise? Rookie dude, stfu.

“Er, uh, yes. It turns out to be electronics– or sterics effect– or maybe both.”

IC50s and SAR are the only descriptor I go by when talking potency, but a lot of us use these kinds of images to try and decide what to make next… So what the heck if you’ve got a carbonyl nearby why not drop an aryl chloride near it and see what happens. If it works, make the tolyl and see if the data holds. There you have your answer.

Wyeth’s series of TPL2 examples might be an illustration of the effect, but I can really only think of a handful of examples in my experience where chlorides were found non-isosteric to methyls.

On the qualitativity of structures. Lets be real here, all this stuff is after the fact rationalization, but I think our analysis depends on a combination of how good the resolution of the xray and how close the two atoms are. Anything under 3A indicates there is something more then Van der Waals going on. 2VAG has a chloride 2.94A away and the resolution of the structure is good at 1.8A.

I can see an electrostatic interaction here, but can we make it a drug?
on October 21, 2007 at 9:18 am10 rookie

Bloggy noise.. KinasePro dude, you know my kidding….
I meant you need good bloggers here like millshake in chemistry (but not in NMR, totally medicinal might be
a suitable one). From my Rookie’s viewpoint, QSAR is noth…ing if a methyl group hits in the air. My question
is here how pheny-O—Cl can attract each other to get binding a…ff..inity as strong as a hydrogen bond?
Do you know any academic people are working there?
on October 21, 2007 at 12:26 pm11 Wavefunction

Ladies and gentlemen, this goes back to an old question; what is a bond?
Like it is for a hydrogen bond, strength depends on geometry and conformation. Optimum values of these can lead to a strong interaction.
on October 21, 2007 at 3:09 pm12 braf.v600e

Without generalizing to every Halogen interaction, I have seen SAR trends that show a Halogen does something that no other atom is able to do in terms of potency and selectivity. To paraphrase, …unique combination of electronics and sterics…
on October 21, 2007 at 5:23 pm13 moody blue

KP:

When you say there is an electrostatic interaction between O and Cl, do you mean the Cl here has partial + charge? Is that common for Ar-Cl? Is is sort of charge distribution influenced by other substituents on the aromatic ring? For example, does the other Cl atom have any effect on this? Thanks.
on October 21, 2007 at 7:48 pm14 kinasepro

I’d postulate that its a special form of induced dipole, but I really don’t know.

The PNAS article that Wavefunction refers to is interesting though.
on October 21, 2007 at 10:38 pm15 Wavefunction

A Pharmacophore Map of Small Molecule Protein Kinase Inhibitors
Malcolm J. McGregor
Web Release Date: 17-Oct-2007; (Article) DOI: 10.1021/ci700244t
on October 22, 2007 at 8:15 am16 kinasepro

Y’know, oxidative insertion is another well known process which puts electrons into an aryl halide bond.

It’s usually described as a stepwise single electron phenomena, but I wonder if the sar of the Grignard reaction wouldn’t give a clue as for what to make next…
on October 22, 2007 at 2:20 pm17 More on the halogen bonding theme « TotallyMedicinal

[...] @ 6:20 pm KinasePro has a bit of discussion going on about halogen bonding in his Cl—-O thread. So I thought I could chip in my tuppence worth, being someone who up till now has had little [...]
on October 23, 2007 at 12:24 pm18 Wavefunction

Structural Competition between Hydrogen Bonds and Halogen Bonds
Christer B. Aakeröy,* Meg Fasulo, Nate Schultheiss, John Desper, and Curtis Moore
J. Am. Chem. Soc., ASAP Article 10.1021/ja073201c
on October 23, 2007 at 1:16 pm19 Wavefunction

…Who is the fairer of them?; X or H?…a fair bit of discussion at Kinasepro and…
on October 28, 2007 at 10:28 pm20 braf.v600e

This article addresses some of the theoretical aspects of halogen bonding:

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17361403&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus