Intramolecular Hydrogen Bonds, We Hardly Knew Thee

Intramolecular hydrogen bonds (IHBs) are interesting beasts. They can be used to improve the potency of a drug by constraining it in a bioactive conformation, and they can be used to hide polarity and improve permeability; cyclosporin being the classic example of the latter.

But the exact amount of potency gain you get through formation of an intramolecular hydrogen bond is not clear. Conformationally you could constrain a molecule through an IHB, but you would still be introducing polarity and hydrogen bond donors and acceptors, and this will lead to some desolvation penalties that would have to be exactly compensated for by the IHB to lead to a net positive effect. There's a group from D. E. Shaw and AstraZeneca who have now looked at about 1200 cases of matched molecular pairs and their biological activities to figure out the contribution of IHBs to potency. The average gain they see? Close to zero. This means that on average, an IHB is as likely to blunt your potency as it is to improve it.

What's more interesting are the outliers. A small but distinct fraction of results display matched molecular pairs in which there is a gain of at least 2 to 3 log units. Inspection of these results sheds light on why these cases really benefit from the formation of IHBs, but it's also important to not overemphasize the positive role of the IHBs in every instance, especially in cases where the non-IHB matched pair displays particular severe repulsive interactions. 

For instance there's an N-Me vs N-H pair in which the latter can form an IHB while the former cannot. But not only can the former not form this bond, the N-Me probably causes a steric repulsion and causes a very different conformational profile, perhaps leading to a conformational penalty in binding to the target. Similarly in another case, the matched pair presents an N-H vs O difference. Here again, not only can the oxygen not form the bond, but it likely strongly repels the other oxygen participating in the IHB. Thus, these outliers are outliers not because the IHB is particularly stable, but because the complementary arrangement is particularly unstable.

Nonetheless, this is a nice study to keep in mind every time you want to use an IHB as a tactic for improving potency or permeability. It may well work, but then it may well not. As in most cases in drug discovery, the decision to incorporate an IHB-forming element will be dictated by many other factors including cost, resources and synthetic accessibility. As with many other tactics in the field, when it comes to IHBs, caveat emptor.

High-throughput method for detecting intramolecular hydrogen bonds (IHBs)

We have talked about the importance of intramolecular hydrogen bonds (IHBs) as motifs to hide polar surface area and improve the permeability of molecules a couple of times here. The problem is that there's no high-throughput method for detecting these in, say, a library of a thousand molecules. The best method I know is temperature and solvent dependent NMR spectroscopy but that's pretty time consuming. Computational methods can certainly be useful but they can sometimes lead to false positives by overemphasizing hydrogen bonding between groups in proximity.

Now here's a promising new method from Pfizer which could lend itself to high-throughput screening of IHBs. The authors essentially use supercritical fluid chromatography (SFC) to study retention times of molecules with and without IHBs. The solvent system consists of supercritical CO2 spiked with some methanol. They pick a judicious set of matched molecular pairs, each one of which contains a hydrogen bonded and non-hydrogen bonded version. They then look at retention times and find - not surprisingly - that the hydrogen-bonded versions which can hide their polar surface area have lower retention times on the column. 

They corroborate these findings with some detailed NMR studies looking at solvent and temperature dependent chemical shifts. At the beginning, when they plot the retention times vs the total polar surface area (TPSA) they get a nice correlation for non IHB compounds. For compounds with IHBs however, the TPSA is an imperfect predictor; what they find in that case is that a new parameter called EPSA based on the retention time is a better predictor of IHBs compared to TPSA.

This seems to me to be a potentially valuable method for quickly looking at IHBs in relatively large numbers of compounds, especially since we have now started worrying about how to get "large" molecules like macrocycles and peptides across membranes. And I assume every medium or large company will probably have access to SFC, so the technology itself should not pose a measurable barrier. One more handy tool to look at "beyond rule of five" compounds.

Reference: 

A High Throughput Method for the Indirect Detection of Intramolecular Hydrogen Bonding

Gilles H Goetz, William Farrell, Marina Shalaeva, Simone Sciabola, Dennis P Anderson, Jiangli Yan, Laurence Philippe, and Michael J. Shapiro

J. Med. Chem., Just Accepted

Publication Date (Web): March 18, 2014 (Article)

DOI: 10.1021/jm401859b