Fungal Cordyceps Nucleosides and Analogs as Potential Anti-Glioblastoma PD-L1 Inhibitors: An In Silico Multiparameter Optimization (MPO) Design

Immune checkpoint modulation has emerged as a promising strategy in cancer therapy, including the treatment of aggressive tumors such as glioblastoma. Among these targets, programmed death-ligand 1 (PD-L1) plays a key role in tumor immune evasion and represents an attractive target for small-molecule inhibitor development. In this study, a virtual screening approach was applied to identify potential PD-L1 modulators within a library of nucleoside-related compounds and structurally similar molecules. A dataset of 400 compounds was evaluated using molecular docking to predict their binding affinity (free energy values and binding pose) toward PD-L1. The resulting complexes were analyzed to identify nonbond interactions within the hydrophobic pocket formed at the PD-L1 dimer interface. In addition to docking results, physicochemical descriptors associated with drug-likeness and blood-brain barrier penetration were calculated, including lipophilicity, molecular weight, hydrogen bond donors and acceptors, as well as topological polar surface area. To integrate these parameters, a multiparameter optimization (MPO) score was implemented. Finally, molecular dynamics simulations of protein-ligand interactions were performed to explore the structural stability for 100 ns using the most promising ligands. The analysis revealed that several top-ranked compounds exhibited favorable docking scores and physicochemical properties compatible with drug-like behavior. Interestingly, BMS-1, a known PD-L1 inhibitor, was identified among the highest-scoring compounds, supporting the reliability of the MPO protocol. Furthermore, multiple candidates displaying nucleoside-like scaffolds combined with reduced polarity and moderate lipophilicity emerged as promising molecules according to the MPO ranking. Overall, the results suggest that nucleoside-derived scaffolds may represent a viable starting point for the development of small-molecule PD-L1 modulators with potential applicability in glioblastoma therapy.