Targeting neuroblastoma by small-molecule inhibitors of human ALYREF protein: mechanistic insights using molecular dynamics simulations

Abstract

Neuroblastoma is a tumour of the sympathetic nervous system mainly prevalent in children. Many strategies have been employed to target several drug-targetable proteins for the clinical management of neuroblastoma. However, the heterogeneous nature of neuroblastoma presents serious challenges in drug development for its treatment. Albeit numerous medications have been developed to target various signalling pathways in neuroblastoma, the redundant nature of the tumour pathways makes its suppression unsuccessful. Recently, the quest for neuroblastoma therapy resulted in the identification of human ALYREF, a nuclear protein that plays an essential role in tumour growth and progression. Therefore, this study used the structure-based drug discovery method to identify the putative inhibitors targeting ALYREF for the Neuroblastoma treatment. Herein, a library of 119 blood-brain barrier crossing small molecules from the ChEMBL database was downloaded and docked against the predicted binding pocket of the human ALYREF protein. Based on docking scores, the top four compounds were considered for intermolecular interactions and molecular dynamics simulation analysis, which revealed CHEMBL3752986 and CHEMBL3753744 with substantial affinity and stability with the ALYREF. These results were further supported by binding free energies and essential dynamics analysis of the respective complexes. Hence, this study advocates the sorted compounds targeting ALYREF for further in vitro and in vivo assessment to develop a drug against neuroblastoma.

Communicated by Ramaswamy H. Sarma

KEYWORDS:

• Neuroblastoma
• ALYREF
• molecular docking
• molecular dynamics simulation
• principal component analysis

Acknowledgement

The authors thank the Pathfinder Research and Training Foundation (PRTF) for technical training and support. Author NG is thankful to University Grants Commission for fellowship (JRF and SRF). Authors thank Shradheya R. R. Gupta for hos help, critical comments and valuable inputs to the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Data available within the article or its supplementary materials

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.