Partial Least-Squares Discriminant Analysis and Ensemble-Based Flexible Docking of PD-1/PD-L1 Inhibitors: A Pilot Study

[Image: see text] Although mAbs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have achieved remarkable therapeutic potential against multiple types of cancer, it is still of great interest for researchers to develop small-molecule PD-1/PD-L1 inhibitors without the mAb-related disadvantages of no oral bioavailability and poor solid tumor penetration. However, targeting the PD-1/PD-L1 pathway with small molecules is normally considered challenging because of the flat and large interaction surface of the PD-1/PD-L1 complex. In this paper, a total of 2558 PD-1/PD-L1 inhibitors were compiled from recent patents and literatures and then used for exploring the chemical space and structural features of PD-1/PD-L1 inhibitors by partial least-squares discriminant analysis. The results showed that intramolecular H bond, amphotericity indices, radius of gyration, nonbond electrostatic energy, fractional van der Waals surface area of H-bond donors, octanol–water partition coefficient, and molecular weight are the seven key features discriminating the PD-1/PD-L1 inhibitors from noninhibitors, with the prediction accuracy larger than 0.90. Based on the seven crystal structures of the PD-L1 dimer complexed with the patent BristolMyers Squibb (BMS) inhibitors, the feasibility of molecular docking for this unconventional binding pocket was further investigated. The results showed that the ensemble-based flexible docking protocol can reproduce the near-native binding conformations of the BMS inhibitors with a strong correlation between the IC(50) values and ligand–receptor interaction energies (R = 0.81). In general, this paper delineates, for the first time, the characteristic features of the PD-1/PD-L1 inhibitors as well as a high-quality flexible docking strategy for the unconventional binding pocket of the PD-L1 dimer.