Ligandability And Target Selection
The druggability of a protein target is defined as the relative ease or difficulty of developing a small molecule that can effectively modulate the protein’s activity in vivo. The ligandability of a protein is defined as the relative ease or difficulty of developing a small molecule that can inhibit the protein in vitro.
This is an important difference, as there are complex pharmacodynamic and pharmacokinetic factors that influence druggability but not ligandability. Our work has focused on quantifying the thermodynamics of surface water molecules to identify hot spots that are amenable to small-molecule binding. The main driving force for binding at PPIs is the loss of water molecules from hydrophobic surfaces and their release into bulk.
This is the oft-cited hydrophobic affect and it includes an interplay of enthalpy and entropy. Importantly, if the water molecules in the unbound state are ignored, major determinants of binding are ignored.
Quantitative metrics for drug target ligandability
Sinisa Vukovic, David J. Huggins
Drug Discovery Today
Exploring the Role of Water in Molecular Recognition: Predicting Protein Ligandability Using a Combinatorial Search of Surface Hydration Sites
Sinisa Vukovic, Paul E Brennan, David J Huggins
Journal of Physics: Condensed Matter - 2016
Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions
Luca Laraia, Grahame McKenzie, David R Spring, Ashok R Venkitaraman, David J Huggins
Chemistry & Biology - 2015