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