Unlocking the therapeutic potential of nolatrexed in glioblastoma multiforme through quantum mechanics, network pharmacology, molecular docking and ADMET analysis.

Introduction: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor that remains challenging to treat due to its resistance to conventional therapies. Despite advances in cancer research, GBM patients face low survival rates often surviving only a few months to a year after diagnosis. Nolatrexed shows notable pharmacological effects and promising therapeutic potential. We explore its interactions, pharmacokinetics and toxicity using computational tools Methods: In-silico investigations were conducted to analyse nolatrexed interactions with GBM targets using network pharmacology which identifies potential targets. The target nolatrexed was optimised and geometry was calculated for the Frontier molecular orbitals (FMO) and visualised using the 6-311(+)G(d)(p) basis set in Gauss View 16. Autodock tools 1.5.7 used for molecular docking, and the results were subsequently validated using Discovery Studio 4.5. ADMET analysed through ADMETlab 2.0, druglito and toxicity estimation software tool (T.E.S.T) . Result: In this study, FMO calculation was performed using Gaussian software were HOMO and LUMO ranges from 2.7059 to 7.9185 eV and shows higher energy gap signifies greater stability and lower reactivity The potential molecular targets of nolatrexed were first identifed using the Swiss Target Prediction platform and pathogenic targets of GBM were identifed using the Genecard, DisGeNET, and CTD database. Followed by compound and disease target overlapping, 69 targets were placed in that JUN, HSP90AA1, STAT3, MTOR, HSP90B1, IGF1R, GSK3B, JAK2, MAP2K1, and SIRT1 were the top-ranked target, which was estimated by CytoHubba plug-in. The molecular docking was performed for nolatrexed towards top 3 genes include mTORC1, mTORC2 and MAP2K1 from the PDB:7YRJ, 7TZO, 5HZE target. The binding score of nolatrexed were – 8.04 kcal/mol and – 7.2 kcal/ mol and -7.69 kcal/ mol respectively. Conclusion: Nolatrexed plays significant role in treatment of brain tumour, which helps to reduce GBM severity. Our findings suggest that nolatrexed hold promise as a potential therapy for GBM.