In silico repurposing of FDA-approved drugs as multi-target inhibitors of glioblastoma

Glioblastoma is a brain tumor with a poor survival rate despite expensive care with Temozolomide and radiotherapy treatment. This necessitates a scientific inquiry into novel, inexpensive, and safer means of treatment. Therefore, this study explored pre-existing medications that could be repurposed for glioblastoma treatment. Three key targets were identified in the literature, retrieved from the Protein Data Bank, and prepared using Biovia Discovery Studio, USCF Chimera, and PyRx software. Drugs approved by the Food and Drug Administration were retrieved from DrugBank, filtered, and prepared for docking. Molecular docking was conducted using the Autodock Vina plugin of PyRx. The drugs' absorption, distribution, metabolism, excretion, and toxicity profiles were assessed using AdmetLab 2.0 and SwissADME. Molecular dynamic simulation (MDS) was conducted using the Desmond software. Twenty-three ligands were identified (the top 10 for each target) that exhibited lower binding energies with the targets than the standard drugs, namely Afatinib, Nutlin-3 and Ivosidenib. Specifically, Belumosudil, Mizolastine, Cyproheptadine, Alectinib, Vorapaxar, Eplerenone, and Risdiplam formed promising receptor-ligand complex with the targets with docking scores ranging from -11.0 kcal/mol to -9.3 kcal/mol while the standard drugs ranged from -9.6 kcal/mol to -5.9 kcal/mol. All the ligands were predicted to be orally bioavailable in humans with a high gastrointestinal absorption rate. The MDS analysis showed that Mizolastine inhibits active sites of EGFR and MDM2 proteins, while Cyproheptadine inhibits those of mutant IDH1 protein, forming stable complexes as potential drug leads for glioblastoma. Thus, Mizolastine and Cyproheptadine are recommended for further in vivo and in vitro assays to consolidate these findings.