Friday, October 1, 2010

Molecular Interactions

Molecular interactions are an important part of the theoretical framework of modern drug discovery and studying them is a great way to increase your understanding of physicochemical principles of molecular design. One view of molecular design is as a process of tuning the interactions of molecules with the different environments in which they exist. Needless to say, knowledge of molecular interactions is particularly valuable in FBDD. Three Roche scientists have recently published �A Molecular Chemist�s Guide to Molecular Interactions� which should be of interest to anyone working in molecular design and other bloggers ( Derek | Joerg ) have already highlighted the article.

The authors cover plenty of ground and everybody should find their favourite molecular interactions discussed. Given the recent LinkedIn discussion on the value of measuring enthalpy and entropy changes associated with binding, I was pleased to see that the authors noted that interpretation of these quantities is typically difficult. The discussion of cooperativity was useful because we often assume that contributions of interactions to binding are additive.

One of my favorite interactions is halogen bonding and I am pleased to see it discussed in some detail. The halogens all confer a degree of hydrophobicity on a molecule and the heavier halogens (i.e. not fluorine) also exhibit an ability to interact with hydrogen bond acceptors that increases with atomic number. Although this class of interaction is sometimes thought to have been discovered in recent times, it�s actually been around a long time. I can remember learning, as a schoolboy in Port of Spain in the mid-1970s, about why iodine is more soluble in aqueous potassium iodide than in water. I developed this theme a bit more in a light-hearted survey of halogens at EuroCUP in 2008 which starred both Bismarck and a medical writer by the name of Bouchardat who was active in Paris when Pincess Victoria became Queen Victoria. I'm not sure if they ever caught the notorious Parisian dog-poisoner.

Something that I found disappointing was that there was not a lot of information about how much additional affinity you�re likely to get by making the different interactions. This should not be seen as a criticism of the authors who have carried out an impressive trawl of the literature. It�s just disappointing that the information is not available in the current literature base.

I�ve some comments to make on the discussion of hydrogen bonds. There is a widely accepted view that the maximum contribution to affinity that a hydrogen bond between a neutral donor and acceptor can make is just over a log unit and here�s what the Roche authors had to say on the subject:

�Hydrogen bonds always convey specificity to a recognition process but do not always add much binding free energy. Desolvation of the donor and the acceptor must occur for the hydrogen bond to form, such that the effects of hydration and hydrogen bond formation nearly cancel out�

I certainly agree that in some cases the contribution of hydrogen bonds to affinity will be minimal. However, the dataset from which that figure of just over a log unit was derived is actually quite small and not especially diverse in terms of donor-acceptor pairings. I believe that if you can form the hydrogen bond deep in a binding pocket then it can make more than the widely accepted maximum contribution to affinity. We recently published inhibition data which included the example of aza-substitution of a pyridine ring resulting in increases of potency of about two log units against Cathepsins S and L2. Some caution is required in interpreting these results because we didn�t have the relevant crystal structures and the inhibitors are racemic. However, I do believe that these results should make us question the prevailing view of the maximum contribution that a hydrogen bond between a neutral donor and acceptor can make to affinity.

I�ll say some things about the discussion of the hydrogen bonding of sulfonyl groups because it should get you thinking a bit. The authors state that:

�Only 30% of the sulfones and sulfonamides form hydrogen bonds. This raises the question of which type of interaction this functional group prefers.�

I�m not sure that I agree with the second sentence and would be interested to know how many of these sulfones and sulphonamides actually had the opportunity to accept a hydrogen bond. If no hydrogen bond donors are present in a molecule then you can�t really blame the sulfonyl oxygens for making contact with aliphatic carbon in the solid state since that's going to be a better option than getting in the way of the sulfonyl oxygens of a lattice neighbour. Even when a donor is present in the molecule, the favoured interaction may well be with a stronger acceptor than the sulfonyl oxygens.

The authors also took a look at the environments of sulfonyl groups in the PDB and here�s what they had to say.

�Notably, of the sulfonyl groups situated in a hydrophobic environment in the PDB, only 36% are found to interact simultaneously as a hydrogen bond acceptor but 79% of the hydrogen-bonded sulfonyl groups are found to interact simultaneously with a hydrophobic group. These findings clearly indicate a dual character of the weakly polar sulfonyl groups as a hydrogen bond acceptor and as a hydrophobic group.�

I simply don�t buy this idea of sulfonyl oxygens having a dual acceptor-hydrophobic character. Hydrophobicity is a statement of aquous solvation characteristics. It will be easier to place a weak acceptor in a hydrophobic environment than it will to place a strong acceptor there. However, if it�s an acceptor, it�ll still prefer the aqueous environment. Think about the consequences of one of these oxygens accepting a hydrogen bond. When an oxygen atom is hydrogen bonded its ability to accept a second hydrogen bond is likely to be reduced because the donor polarises the acceptor oxygen. Also the second donor will also experience repulsive secondary electrostatic interactions with the existing donor. Provided that the oxygen can still accept a hydrogen bond, it will not be too �distressed� (apologies for anthropomorphising) to be in contact with hydrophobic surface. If you�re interested in this sort of thing then take a look at our article on alkane/water partition coefficients to see how accepting a hydrogen bond (from methanol which we used to model octanol) is likely to affect the ability of carbonyl oxygen to accept a second hydrogen bond.

To be fair, the authors do recognise that accepting a hydrogen bond might affect the probability of a sulfonyl oxygen atom making contact with hydrophobic surface. However, this hydrogen bond donor doesn�t need to come from the protein or a water molecule that the crystallographers can see. How many of the sulfonyl oxygen atoms which lack �visible� hydrogen bonds are sufficiently solvent-exposed to accept hydrogen bonds from �invisible� solvent water molecules? I�ll leave it to you the reader to think about whether analysis of the CSD (as opposed the PDB) has any relevance to hydrophobic interactions.

I�m now going to wrap up with what will be seen by some to be nitpicking although that is not my intention. This is what the authors have to say about QM calculations and hydrogen bonding:

�Where experimental data are not available, acceptor strengths can be obtained from quantum chemical calculations.�

My first criticism of this statement (which is getting very close to nitpicking although as The Blogger I�m allowed to do that) is that quantum chemical calculations can be used to predict donor strengths as well. Like they might say in Buenos Aires, it takes two to tango. My second criticism is that rather than talking about generic �quantum chemical calculations� the authors could also have mentioned that electrostatic potential is a useful predictor of both acceptor and donor strength. I have to declare an interest here as author of reference 98d but I do believe that the effectiveness of electrostatic potential as a predictor of donor and acceptor strength is more important than whether it was calculated quantum mechanically or classically. It tells us something about the nature of the hydrogen bond.

That brings us to the end of my review. The article is definitely a good read and a valuable contribution to the field. To put it bluntly, you need to know this stuff if you want to succeed in FBDD. I�ve flagged up the issue of sulfonyl oxygen hydrogen bonding to hopefully make you think a bit and maybe even generate some discussion. Feel free to make comments of your own.

Literature cited

Bissantz, Kuhn & Stahl, A Medicinal Chemist�s Guide to Molecular Interactions. J. Med. Chem. 2010, 53, 5061-5084 DOI

Davis & Teague, Hydrogen Bonding, Hydrophobic Interactions, and Failure of the Rigid Receptor Hypothesis Angew. Chem. 1999, 38 736-749 DOI

Bethel et al, Design of selective Cathepsin inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 4622-4625 DOI

Toulmin, Wood & Kenny, Toward Prediction of Alkane/Water Partition Coefficients. J. Med. Chem. 2008 51, 3720-3730 DOI

Kenny, Hydrogen bonding, electrostatic potential and molecular design. J. Chem. Inf. Model. 2009, 49, 1234-1244 DOI