Characterization of PD-L1 binding sites by a combined FMO/GRID-DRY approach

The programmed cell death protein 1 (PD-1) and its ligand, PD-L1, constitute an important co-inhibitory immune checkpoint leading to downregulation of immune system. Tumor cells developed a strategy to trigger PD-1/PD-L1 pathway reducing the T cell anticancer activity. Anti-PD-L1 small drugs, generally with improved pharmacokinetic and technological profiles than monoclonal antibodies, became an attractive research topic. Nevertheless, still few works have been published on the chemical features of possible binding sites. In this work, we applied a novel computational protocol based on the combination of the ab initio Fragment Molecular Orbital (FMO) method and a newly developed GRID-DRY approach in order to characterize the PD-L1 binding sites, starting from PD-1/PD-L1 and PD-L1/BMS-ligands (Bristol–Mayers Squibb ligands) complexes. The FMO method allows the calculation of the pair-residues as well as the ligand–residues interactions with ab initio accuracy, whereas the GRID-DRY approach is an effective tool to investigate hydrophobic interactions, not easily detectable by ab initio methods. The present GRID-DRY protocol is able to determine the energy contributions of each ligand atoms to each hydrophobic interaction, both qualitatively and quantitatively. We were also able to identify the three specific hot regions involved in PD-1/PD-L1 protein–protein interaction and in PD-L1/BMS-ligand interactions, in agreement with preceding theoretical/experimental results, and to suggest a specific pharmacophore for PD-L1 inhibitors.