Abstract
Small molecules that regulate protein-protein interactions can be valuable drugs; however, the development of such small molecules is challenging as the molecule must interfere with an interaction that often involves a large surface area. Herein, we propose that modulating the conformational ensemble of the proteins participating in a given interaction, rather than blocking the interaction by directly binding to the interface, is a relevant strategy for interfering with a protein-protein interaction. In this study, we applied this concept to P-cadherin, a cell surface protein forming homodimers that are essential for cell-cell adhesion in various biological contexts. We first determined the crystal structure of P-cadherin with a small molecule inhibitor whose inhibitory mechanism was unknown. Molecular dynamics simulations suggest that the inhibition of cell adhesion by this small molecule results from modulation of the conformational ensemble of P-cadherin. Our study demonstrates the potential of small molecules altering the conformation ensemble of a protein as inhibitors of biological relevant protein-protein interactions.