Cl – - – - O
Posted by kinasepro on October 18, 2007
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.
The animation shows their earlier 1z57 with Hymenialdisine, a somewhat more traditional kinase inhibitor.
Wavefunction said
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.
braf.v600e said
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…
Chris said
How did you generate the image? I’ve been debating whether to start using Jmol but my javascript is very rusty.
kinasepro said
I use pymol, photoshop, and chemdraw to generate all the images around here.
rookie said
How does the CL—O interaction happen as that
of N-H—-O? Any expert can explain it?
rookie said
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’?
braf.v600e said
ImageJ is a good open source alternative to photoshop:
http://rsb.info.nih.gov/ij/
milkshake said
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.
kinasepro said
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?
rookie said
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?
Wavefunction said
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.
braf.v600e said
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…
moody blue said
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.
kinasepro said
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.
Wavefunction said
A Pharmacophore Map of Small Molecule Protein Kinase Inhibitors
Malcolm J. McGregor
Web Release Date: 17-Oct-2007; (Article) DOI: 10.1021/ci700244t
kinasepro said
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…
More on the halogen bonding theme « TotallyMedicinal said
[...] @ 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 [...]
Wavefunction said
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
Wavefunction said
…Who is the fairer of them?; X or H?…a fair bit of discussion at Kinasepro and…
braf.v600e said
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