A structure-based virtual screening study to identify potential inhibitors targeting the TKB domain of CBL-B

CBL-B is an E3-ubiquitin ligase that serves a key role in modulating immune response by negatively inhibiting effector T-cell activation. Inhibitors of CBL-B would be an effective way for immune activation, making it a promising target for cancer immunotherapy and other related immune diseases. In this study, we sought to identify potential inhibitors of CBL-B through structure-based virtual screening, molecular docking, ADMET analysis, molecular dynamics simulation, and MM/GBSA calculations. A diverse set of compounds was screened against CBL-B using molecular docking augmented by a machine-learning scoring function (RF-score). The top leads were further evaluated for their ADMET properties resulting in three compounds that were subjected to a 100 ns MD simulation. MD results revealed the stability of protein-ligand complexes. Finally, MM/GBSA calculations resulted in higher free binding energy for the three compounds compared to the cocrystallized ligand, implying better affinity towards CBL-B and suggesting the use of these compounds as novel inhibitors of CBL-B.