揭示ALK蛋白对儿童癌症破坏性影响背后的分子机制:通过计算机预测、分子对接和动力学研究了解有害snp

Abdulhadi Almazroea
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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. 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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. 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引用次数: 0

摘要

儿童癌症在诊断和治疗方面面临重大挑战,间变性淋巴瘤激酶(ALK)蛋白已成为这些恶性肿瘤的关键分子靶点。ALK是一种酪氨酸激酶受体,在正常的细胞过程中起着至关重要的作用,但ALK基因的遗传改变和异常激活与各种儿童癌症类型有关。虽然遗传改变已经得到了很好的研究,但ALK蛋白在儿童癌症中致病性的确切分子机制仍然知之甚少。在本研究中,主要目的是揭示有害单核苷酸多态性(snp)对ALK蛋白结构和功能影响的相关分子机制。材料和方法利用已知的几个ALK蛋白点突变进行计算机预测,如polyphen2、SIFT、PANTHER、PredictSNP等,利用Consurf server进行残基守恒分析,分子对接(AutoDock)和分子动力学模拟研究(GROMACS)。结果计算预测发现,所研究的变异在不同的工具中是有害的。残基保守性分析表明,所有变异都位于高度保守区域。野生型和突变型结构与克唑替尼药物分子的分子对接研究发现,这些变异调节了结合腔,对结合亲和力有很强的影响。野生型的结合能为-5.896 kcal/mol,而突变型的结合能为-9.988 kcal/mol。发现野生型的特异性氨基酸Ala1200与克唑替尼相互作用,Asp1203残基在突变体结构中主要相互作用。结论仿真研究从结构稳定性和残差波动两方面区分了变异体。在研究的变异中,R1275Q、F1245V和F1174L根据计算机预测具有很强的有害作用、结构变化和致病性。通过阐明ALK基因中有害突变的功能后果,本研究可能为儿科癌症的治疗发现新的治疗靶点和个性化的医学方法。最终,深入了解ALK蛋白在驱动反应和耐药性中的分子机制将有助于改善患者的治疗结果,并促进我们对这种复杂疾病的理解。
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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 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.
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来源期刊
CiteScore
0.40
自引率
0.00%
发文量
91
期刊介绍: The journal will cover technical and clinical studies related to medical and pediatric oncology in human well being including ethical and social issues. Articles with clinical interest and implications will be given preference.
期刊最新文献
Clinical Outcomes of Crizotinib Readministration in Patients with Nonsmall Cell Lung Cancer with Anaplastic Lymphoma Kinase Rearrangement: Case Report and Review of Literature Advanced Pediatric-Type Follicular Lymphoma, Consequences of a Late Presentation in a Resource-Poor Setting: Case Report and Literature Review Renal Inflammatory Myofibroblastic Tumor in an Infant: Case Report with Review of Literature Primary Resistance to ALK Inhibitors in a Patient with Nonsmall Cell Lung Cancer with ALK Rearrangement: A Case Report with Review of Literature Approach to Diagnosis of BCR::ABL1 -Negative Myeloproliferative Neoplasms
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