Inhibiting protein-protein interactions 2

Published on April 2, 2014   35 min

A selection of talks on Pharmaceutical Sciences

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I want to spend a few minutes talking about a different view of druggability, a different way of thinking about the relationship between the structure of approaching surface and its potential to bind small molecule ligand.
This concept relates to proposition 4, the proposition that the druggability of a protein/protein interaction target can usefully be thought of as its potential ligand deficiency.
The idea of ligand deficiency goes back to a seminal paper published by Kuntz et al in 1999. In this study, the authors analyzed a large number of ligands for proteins for which there were reliable affinity values reported in the literature. And what they showed-- as illustrated on the figure shown here, which I took from that paper-- is that the amount of binding energy that a ligand can generate with its target correlates with the size of the ligand, as quantified here in terms of the number of heavy atoms, the number of non-hydrogen atoms in the ligand structure. And you can see that this relationship appears to saturate. But at the lower extreme shown by the solid line in the figure, you can see that for each additional heavy atom of ligand structure, and additional up to 1.5 kilocalories per mole of binding energy can be generated. That corresponds to an increase in binding affinity of more than tenfold for the addition of each additional heavy atom of ligand structure.
The relationship between the size of a ligand and the amount of binding energy it can generate is quantified with a view to its utility for drug discovery by Hopkins and Groom in 2004, and substantially extended by Phil Hajduk from the Abbott group a few years later. And the bottom line here is that if you imagine a typical drug has a molecular weight less than 500 atomic mass units, and typically will have a binding affinity of at least 10 nanomolar in order to be pharmacologically active, this corresponds then to about 0.3 kilocalories per mole of binding energy generated per heavy atom, per non-hydrogen atom present in that drug structure. And this ratio of binding energy to ligand heavy atoms is known as the ligand efficiency. The higher that number is, the more binding energy the ligand is generating for its size, and therefore the more efficiently it is extracting binding energy from its interaction with the protein, and the more strongly it will bind.