Unveiling the Molecular Mechanisms Behind the Devastating Impact of the ALK Protein on Pediatric Cancers: Insights into Deleterious SNPs through In Silico Predictions, Molecular Docking, and Dynamics Studies

Abstract

Abstract Introduction Pediatric cancers present significant challenges in terms of diagnosis and treatment, and the anaplastic lymphoma kinase (ALK) protein has emerged as a crucial molecular target in these malignancies. ALK, a receptor tyrosine kinase, plays a vital role in normal cellular processes, but genetic alterations and aberrant activation of the ALK gene have been implicated in various pediatric cancer types. While genetic alterations have been well studied, the precise molecular mechanisms underlying the pathogenicity of the ALK protein in pediatric cancers remain poorly understood. Objective In this study, the primary objective is to uncover the molecular mechanisms associated with the effects of deleterious single-nucleotide polymorphisms (SNPs) on the structure and functionality of the ALK protein. Material and Methods Several known point mutations of the ALK protein were taken for the in silico predictions such as PolyPhen-2, SIFT, PANTHER, PredictSNP, etc., residue conservation analysis using Consurf server, molecular docking (AutoDock), and molecular dynamics simulation studies (GROMACS). Results The computation predictions found that the studied variants are deleterious in different tools. The residue conservation analysis reveals all the variants are located in highly conserved regions. The molecular docking study of wild-type and mutant structures with the crizotinib drug molecule found the variants were modulating the binding cavity and had a strong impact on the binding affinity. The binding energy of the wild-type is –5.896 kcal/mol, whereas the mutants have –9.988 kcal/mol. The specific amino acid Ala1200 of wild-type was found to interact with crizotinib, and Asp1203 residue was found to interact predominantly in the mutant structures. Conclusion The simulation study differentiates the variants in terms of structural stability and residue fluctuation. Among the studied variants, R1275Q, F1245V, and F1174L had strong deleterious effects, structural changes, and pathogenicity based on the in silico predictions. By elucidating the functional consequences of deleterious mutations within the ALK gene, this research may uncover novel therapeutic targets and personalized medicine approaches for the management of pediatric cancers. Ultimately, gaining insights into the molecular mechanisms of the ALK protein's role in driving response and resistance will contribute to improving patient outcomes and advancing our understanding of this complex disease.