DEVELOPMENT OF A TECHNOLOGICAL PLATFORM FOR THE IDENTIFICATION OF MODULATORS FOR PED/PEA15 PROTEIN-PROTEIN INTERACTIONS

PED/PEA15 is overexpressed in type II diabetes, where its interaction with phospholipase D1 (PLD1) impairs insulin-stimulated glucose transport, making this protein–protein interaction an attractive therapeutic target. A molecular fragment, BPH03, was previously identified as a promising scaffold capable of modulating the PED/PEA15–PLD1 interaction by binding to a hidden druggable pocket at the interface. In this study, Bio-SAXS analyses were performed to obtain a three-dimensional model of PED/PEA15, a protein characterised by a partially disordered C-terminal tail. Scattering data collected at the EMBL P12 beamline and analysed with the ATSAS suite revealed a semi-folded conformation of the protein, enabling the generation of a hybrid SAXS–NMR structural model. This model was subsequently used for in silico studies, including induced-fit docking, MM-GB/SA rescoring, and molecular dynamics simulations, to characterise the binding of a second fragment, F242. The results identified a stable binding mode within the same pocket targeted by BPH03, involving key residues at the PED/PEA15 interaction interface. Overall, these findings demonstrate the druggability of PED/PEA15 and highlight biphenyl-based fragments as promising starting points for the rational design of inhibitors targeting PED/PEA15-mediated protein–protein interactions relevant to type II diabetes and cancer.