Identification of Targeted Therapeutic Compounds for the treatment of Traumatic Brain Injuries: An in-Silico Study

Ali Akbar Esfahani, Mohammad; Faghih, Hossein; Zamani Amirzakaria, Javad; Talebi, Samira; Eslamian, Mohammad; Rasouli, Hamid Reza; Ahmadpour, Fathollah

doi:10.30491/tm.2025.538185.1859

Identification of Targeted Therapeutic Compounds for the treatment of Traumatic Brain Injuries: An in-Silico Study

Document Type : Original Article

Authors

Mohammad Ali Akbar Esfahani ¹^{, 2}

Hossein Faghih ¹

Javad Zamani Amirzakaria ³

Samira Talebi ³

Mohammad Eslamian ¹

Hamid Reza Rasouli ¹

Fathollah Ahmadpour ¹

¹ Trauma Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.

² Department of Genetics, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

³ National institute of genetic engineering and biotechnology, Tehran, Iran

10.30491/tm.2025.538185.1859

Abstract

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 E2-related factor 2 (Nrf2) 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 E2-Related Factor 2 for TBI management.
Methods: The compounds that inhibit Nrf2 degradation by suppressing Nrf2 inhibitors, such as Kelch-like ECH-associated protein 1 (Keap1), E3 ligase adapter β-TrCP, and glycogen synthase kinase 3 (GSK-3), 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 Nrf2 degradation (Keap1, GSK-3, and β-TrCP proteins) with over 274000 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 2020.1 was performed.
Results: Four molecules, including ZINC435885061, ZINC469515563, ZINC119772060, and ZINC550706912, can suppress all three Nrf2 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 Nrf2 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.

Keywords

Traumatic brain injury

nuclear factor E2-related factor 2 (Nrf2)

virtual screening

molecular docking

Nebivolol

Subjects