Investigation of molecular interactions and structural stability of ALK tyrosine kinase inhibitors: A molecular dynamics simulation study

Mohammadi Mousavi, Sayed Sadegh; Arab, Seyed Shahriar

doi:10.48311/biot.2025.27536

Investigation of molecular interactions and structural stability of ALK tyrosine kinase inhibitors: A molecular dynamics simulation study

Document Type : Original Research

Authors

Sayed Sadegh Mohammadi Mousavi

Seyed Shahriar Arab

Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

https://doi.org/10.48311/biot.2025.27536

Abstract

Anaplastic lymphoma kinase (ALK) is an important target in the treatment of cancer, especially non-small cell lung cancer (NSCLC) with gene rearrangements. In this study, the effects of three tyrosine kinase inhibitors (TKIs) including Crizotinib, Ceritinib, and Alectinib on the ALK tyrosine kinase domain were investigated and compared using molecular dynamics (MD) simulations. Various analyses such as RMSD, radius of gyration (RG), solvent accessible surface area (SASA), hydrogen bond number (Hbond), principal component analysis (PCA), and MMPBSA were used in this study.
Molecular dynamics simulations for 100 ns showed that Alectinib resulted in structural stability, reduced solvent accessible surface area (SASA) compared to Crizotinib and Ceritinib, and greater protein compaction. MMPBSA results also indicated a lower binding free energy and higher binding affinity of Alectinib to ALK, which enhances its efficacy. The use of Alectinib, due to its high ability to cross the blood-brain barrier and its effect on brain metastases, can improve treatment efficacy and reduce drug resistance. These results and findings indicate that Alectinib can be an option for first-line treatment.

Keywords

Anaplastic lymphoma kinase (ALK)

tyrosine kinase inhibitor (TKI)

molecular dynamics (MD) simulations

Alectinib

MMPBSA

Subjects

Bioinformatics

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