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.


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