Modulation of a conformational ensemble by a small molecule that inhibits key protein–protein interactions involved in cell adhesion

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.