Exploring possibilities with PD-L1: protein modulation through in silico investigation of new cavities

PD-L1 is a well-validated pharmaceutical target for cancer treatment, whose inhibitors target the PD1-PDL1 interface1. There is no knowledge about allosteric sites, and investigating cryptic sites is an alternative to expanding the number of druggable pockets of interest2. In this context, in silico approach is a promissory strategy to explore and propose new ligands to a target region3. The cosolvent MD simulation exposed a new cryptic site (drugscore 0.825). Furthermore, we identified the indacaterol as a possible binder to the cavity through drug repositioning. In a complex with PD1-PDL1, the ligand showed a conformational selection-like mechanism that prevented assuming the native conformations. This event indicates that this interaction on the cryptic site could incite an allosteric effect on the protein, corroborated by energetic evaluations. Here, we identified a new cavity with a high potential to modulate PD-L1 that can support the development of new classes of molecules against this target.