Wednesday, 29 June 2011

Lipophilicity teaser

This post got prompted one by Dan at Practical Fragments and I'm going to ask you to first take a look at that and at the comments. Now I'd like you to look at some measured octanol/water logP values that I pulled from the Sangster Research Laboratories logPow database. The question I'd like to put to you is whether you think that these measured logP values truly reflect the energetic costs of moving the different isomeric methylimidazoles from water to a truly non-polar environment like a hydrophobic binding pocket in a protein.

Let's take a look these figures. The least lipophilic compound of the set is N-methylimidazole in which the hydrogen bond donor of imidazole has been capped, although the partition coefficients for the three compounds are all very similar. It seems that the octanol/water partitioning system just doesn't seem to 'see' the hydrogen bond donors of the 2-methyl and 4/5-methyl isomers.

Octanol has a hydroxyl group and, in the context of a shake-flask logP determination, gets pretty wet (~2M), making it a unconvincing model for the hydrophobic core of a lipid bilayer or a hydrophobic binding pocket. In contrast, alkanes lack hydrogen bonding capability which also means that they also dissolve less water. The catch is that alkane/water partition coefficients are more difficult to measure than their octanol/water equivalents since polar solutes are poorly soluble in alkane solvents.

The difference between octanol/water and alkane/water logP values for a compound (often termed ΔlogP) is one measure of the polarity of the compound. The octanol/water logP of phenol is 1.5 and it would be reasonable to describe it as lipophilic. However in the alkane/water system the situation is reversed and the logP of -0.6 would lead to phenol being described as hydrophilic.

I'll leave things here for now because this post is really just a teaser and I will be returning to the theme in more depth in the future. If you're interested in finding out more take a look at my harangue from the March 2011 PhysChem Forum at Syngenta and the article that goes with it. I'd also recommend reading this review by Wolfenden if you're interested in the relevance of alkane/water logP values to protein structure and function.

Literature cited

Toulmin, Kenny & Wood, Toward prediction of alkane/water partition coefficients. J. Med. Chem. 2008, 51, 3720-3730. DOI

Wolfenden, Experimental Measures of Amino Acid Hydrophobicity and the Topology of Transmembrane and Globular Proteins. J. Gen. Physiol. 2007, 129, 357-362. DOI

Saturday, 25 June 2011

FBDD & Molecular Design

The FBDD Literature blog is getting a bit of a makeover. One of the reasons for doing this is that since I escaped from Big Pharma my access to literature has been erratic, making it difficult to maintain the required awareness of the current literature. However, a bigger reason for the changes was to broaden the focus of the blog to include Molecular Design, which is my primary scientific interest.

There is of course a lot of molecular design in FBDD, which I like to think of as little more than a smart way to do structure-based design. Molecular design may be defined as control of properties of compounds and materials through manipulation of molecular properties. Although computational chemistry tools are very useful in molecular design, the essence of design is thinking about molecules and I don’t want people without a CompChem background to be put off by the blog having Molecular Design in its title.

There will still be plenty of fragment-based material in the blog since I will be continuing the series on screening library design which came to a halt on Easter Island a year and half ago. However, I’m also planning some posts on physicochemical properties such as logP and logD which are important in FBDD but have a much broader relevance in Drug Discovery.