Inhibiting protein-protein interactions 2

Published on April 2, 2014   35 min

Other Talks in the Series: Small Molecule Drug Discovery

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.