What is Chemical Similarity, and how is it Useful? (by Edmund Duesbury)

In the final year of my PhD, I have been investigating different forms of alignment of chemicals, and seeing which method is best at predicting whether a chemical will be active against a particular drugtarget.

Similarity is subjective to a particular problem domain.  As an example, which two most objects are most similar – an apple, a pumpkin or a basketball?  All three are more or less spherical, but the pumpkin and apple have the similarity of being fruit, while the pumpkin and basketball are a similar size.

The same subjectivity exists in chemistry.  A common goal when searching for similarity in chemicals is to predict whether one compound will act in the same way as another compound, known to have useful pharmaceutical properties.  The desired “similarity” in this case, is a similarity of biological activity: something which, at present, is impossible to predict.  However, we can attempt to infer such a property from aspects of structural similarity.

Serotonin reuptake inhibitors is a group of chemicals that includes many useful antidepressants. Consider the examples below, of compounds that act as serotonin reuptake inhibitors.  In the first case (Figure 1), similarity is based on the largest common fragment (highlighted in bold).

Figure 1

The similarity here is obvious, the only difference being the Br atom.  However, the same technique fails to show the biological similarity between the two inhibitors in Figure 2.

Figure 2.

In this case, the approach of finding the largest fragment has failed to highlight the “similarity” between the two compounds.  A technique based on finding the maximum possible overlap of edges however, is more successful (Figure 3).

Figure 3.

This method, which seeks to find a set of common fragments emphasises a different “similarity” between these compounds.

Comparing and classifying

Imagine an ignorant northern European, dropped at the edge of a tropical jungle.  He knows only things from his homeland.  In the distance, he sees something as black as a crow.  A gust of wind shakes the nearby trees.  The object sits, solid and unmoving.  It’s obviously not a crow then. 

Against the grey green shade of the trees, the pitch black object stands out.  A nut falls from the canopy.  It hits the object and bounces off.  There is a dull thud.  On a hot day like this, pitch would be soft and sticky.  Whatever sort of black it is, it is not pitch black. 

The man moves closer.  Beside the trees sits a round carved object.  He picks it up.  It looks as black as coal, or as black as jet, but it feels like neither of them. 

The mysterious force that dropped him near the jungle picks him up and whisks him home.  He returns, the proud possessor of an ebony carving and a new source of similes and metaphors.

OK - forgive the somewhat fanciful turn that this blog has taken.  The point that I am labouring to make is that we classify according to what we're familiar with, and that's especially relevant to LIS people.  Thanks to Liz C for not only offering to give a short talk about the classification system of the Warburg Library at the forthcoming researchers' discussion group (Thursday 14/04, 16.30, Rm 324) but also for reminding me of George Lakoff.  His book "Women, Fire, and Dangerous Things" gave me food for thought when I did the MSc here years ago. 

The main event this Thursday however, is a discussion on blogs and their role in research, to be led by Angharad (who's working overtime, since she also contributed to last month's discussion).