Introduction:
Traumatic Brain Injury (TBI) is a significant public health problem. Detecting effective therapeutic compounds for the management of TBI patients is essential. Nuclear factor E۲-related factor ۲ (Nrf۲) is a transcription factor that regulates oxidative stress and inflammation after TBI. This study aimed to assess Targeted Therapeutic Compounds by inhibiting the degradation of Nuclear Factor E۲-Related Factor ۲ for TBI management. Methods: The compounds that inhibit Nrf۲ degradation by suppressing Nrf۲ inhibitors, such as Kelch-like ECH-associated protein ۱ (Keap۱), E۳ ligase adapter β-TrCP, and glycogen synthase kinase ۳ (GSK-۳), were identified by a literature review. Possible active sites for identified target proteins were determined. Molegro Virtual Docker (MVD) software predicted the protein-ligand interaction study. The interaction compounds that inhibit Nrf۲ degradation (Keap۱, GSK-۳, and β-TrCP proteins) with over ۲۷۴۰۰۰ drug-like compounds from the ZINC database were analyzed by molecular docking. Selected compounds from the molecular docking analysis were subjected to ADME prediction for pass drug parameters. The molecules were imported to Swiss Similarity software, and screening was performed using the Food and Drug Administration (FDA) approved drugs library. To assess the structural stability of the hit compounds, molecular dynamics (MD) simulation using the GROMACS package version ۲۰۲۰.۱ was performed. Results: Four molecules, including ZINC۴۳۵۸۸۵۰۶۱, ZINC۴۶۹۵۱۵۵۶۳, ZINC۱۱۹۷۷۲۰۶۰, and ZINC۵۵۰۷۰۶۹۱۲, can suppress all three Nrf۲ inhibitors and are capable of penetrating the blood-brain barrier. The ADME analysis of the compounds showed that these four molecules could be used therapeutically.
Nebivolol is an FDA-approved drug identified for neuroprotective effects and can be used as a potential candidate for treatment.Conclusion: Targeted therapeutic compounds that inhibit Nrf۲ degradation can be used for TBI treatment. Nebivolol, an FDA-approved drug, has neuroprotective effects and can be used for TBI treatment, but further studies, such as animal studies and clinical trials, are necessary.