Molecular Insights into the Binding Interaction of the First Class of Potent Small Molecules Disrupting the YAP-TEAD Protein-Protein Interaction

Disruption of the YAP-TEAD protein-protein interaction is an attractive therapeutic strategy for oncology to suppress tumour progression and cancer metastasis. YAP binds to TEAD at a large flat binding interface (~3500 2) devoid of a well-defined druggable pocket, so it has been difficult to design low molecular weight compounds to abrogate this protein-protein interaction directly. Recently, work by Furet and coworkers (ChemMedChem 2022, DOI: 10.1002/cmdc.202200303) reported the discovery of the first class of small molecules able to efficiently disrupt the transcriptional activity of TEAD by binding to a specific interaction site of the YAP-TEAD binding interface. Using high-throughput in silico docking and structure-based drug design, they identified a virtual screening hit from a hot-spot derived from their previously rationally designed peptidic inhibitor. Given advances in rapid high-throughput screening and rational approaches to peptidic ligand discovery for challenging targets, we analyzed the pharmacophore features involved in transferring from their peptidic to small molecule inhibitor that could enable small molecule discovery for such targets. Here, we show that pharmacophore analysis augmented by solvation analysis of molecular dynamics trajectories can guide the designs while binding free energy calculations provide greater insight into the binding conformation and energetics accompanying the association event. The computed binding free energy estimates agree with experimental findings and offer useful insight into structural determinants that influence ligand binding to the TEAD interaction surface, even for such a shallow binding site. In general, our results provide rationale for the structure-based design efforts in compound optimization that led to a significant gain in potency among the first class of potent small molecule YAP:TEAD protein-protein inhibitors.