Silico analysis of the target and possible mechanism of lomustine in the treatment of primary glioblastoma.

Objective: The targets and mechanism of lomustine in the treatment of primary glioblastoma (PGBM) were investigated by molecular docking and molecular dynamics simulation, which provided theoretical guidance for its clinical application.

Methods: We used the PharmMapper database to identify all of the targets of lomustine, and then examined the effect of lomustine on PGBM using molecular docking, molecular mechanics generalized born surface area (MMGB/SA), gene difference analysis, molecular dynamics simulation, survival analysis, and protein subcellular localization prediction.

Results: A total of 243 lomustine targets and 3197 PGBM-related targets were screened. The intersection of the two was 59 active targets. Protein interaction (PPI), gene enrichment analysis, gene difference analysis, molecular docking, and molecular dynamics simulation finally screened out three effective targets of lomustine, namely HMOX1, AKT1, and EGFR, which exist mainly in the cytoplasm, nucleus, and vesicles, respectively. These three targets mainly inhibit JAK-STAT, PD-1/PD-L1, PI3K-Akt, Rap1, HIF-1, MAPK, and Fc-εRI involved in protein metabolism, the regulation of cell differentiation, the regulation of the Notch signaling pathway and glial cell activation, and other biological processes and could play a role in the treatment of PGBM.

Conclusions: HMOX1, AKT1, and EGFR may represent novel therapeutic targets for lomustine in the clinical treatment of PGBM.