Exploring the potential of Cucurbitacin analogs as HMGB1 inhibitors in glioblastoma multiforme: Insights from molecular docking and MD simulation of various triterpenoids

Glioblastoma multiforme (GBM) is the most aggressive and prevalent central nervous system (CNS) malignancy, characterized by tumor heterogeneity and poor prognosis. In GBM, tumor-induced inflammation, hypoxia, and cellular damage release damage-associated molecular patterns (DAMPs) like High Mobility Group Box 1 (HMGB1). HMGB1 exerts both tumor-promoting and tumor-suppressive effects, its functional outcome is regulated by its subcellular localization, redox state, and the immune cell infiltrate within the tumor microenvironment (TME). In our study, we focus on confirming the protumorigenic role of HMGB1 using bioinformatic tools to further validate its contribution to tumor progression. Therefore, targeted inhibition of HMGB1 seems to be a promising therapeutic strategy. Glycyrrhizin, a triterpenoid, is a known HMGB1 inhibitor. We aimed to create a more effective inhibitor by utilizing structural insights of glycyrrhizin. We used computational screening to evaluate the bioactivity of other potential triterpenoids as HMGB1 inhibitors in the context of GBM. Molecular docking and MD simulation were performed to screen the triterpenoid library. We found that triterpenoids like cucurbitacin E, F, I, and K have a higher potential to bind at the TLR4 and RAGE binding domains of HMGB1 compared to glycyrrhizin. These domains are crucial for HMGB1-receptor interactions, which enhance GBM malignancy. Moreover, drug-likeness and pharmacokinetic analyses of cucurbitacins indicated favorable therapeutic profiles. Our findings advance the discovery of novel HMGB1 inhibitors, improve GBM treatment, and establish a foundation for further validation and clinical applications.