Computational Analysis of Deleterious SNPs in NRAS to Assess Their Potential Correlation With Carcinogenesis

Behairy, Mohammed Y.; Soltan, Mohamed A.; Adam, Mohamed Shaker S.; Refaat, Amal; Ezz, Ehab M.; Albogami, Sarah; Fayad, Eman; Althobaiti, Fayez; Gouda, Ahmed M.; Sileem, Ashraf E.; Elfaky, Mahmoud A.; Darwish, Khaled M.; Eldeen, Muhammad Alaa

doi:10.3389/fgene.2022.872845

Cited by 7 publications

(9 citation statements)

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“…In a recent study by Behairy et al (2022), various SNPs of the HRAS gene were assessed to identify those potentially deleterious and associated with disease development using computational approaches. We searched for nsSNPs against HRAS in SNP databases and found 138 hits.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, using multiple computational tools and integrating their results can provide more reliable predictions of functional nsSNPs, which can aid in understanding the molecular basis of diseases caused by nsSNPs. Overall, the study by Behairy et al (2022), highlights the importance of using computational approaches to identify potential deleterious nsSNPs in genes and their association with disease development. The study also underscores the significance of using multiple computational tools to validate the functional relevance of nsSNPs and the need for further research to establish their association with disease development.…”

Section: Discussionmentioning

confidence: 99%

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Predicting the effects of rare genetic variants on oncogenic signaling pathways: A computational analysis of HRAS protein function

Ali¹,

Ali²,

Qamar³

et al. 2023

Front. Chem.

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The HRAS gene plays a crucial role in regulating essential cellular processes for life, and this gene's misregulation is linked to the development of various types of cancers. Nonsynonymous single nucleotide polymorphisms (nsSNPs) within the coding region of HRAS can cause detrimental mutations that disrupt wild-type protein function. In the current investigation, we have employed in-silico methodologies to anticipate the consequences of infrequent genetic variations on the functional properties of the HRAS protein. We have discovered a total of 50 nsSNPs, of which 23 were located in the exon region of the HRAS gene and denoting that they were expected to cause harm or be deleterious. Out of these 23, 10 nsSNPs ([G60V], [G60D], [R123P], [D38H], [I46T], [G115R], [R123G], [P11OL], [A59L], and [G13R]) were identified as having the most delterious effect based on results of SIFT analysis and PolyPhen2 scores ranging from 0.53 to 69. The DDG values −3.21 kcal/mol to 0.87 kcal/mol represent the free energy change associated with protein stability upon mutation. Interestingly, we identified that the three mutations (Y4C, T58I, and Y12E) were found to improve the structural stability of the protein. We performed molecular dynamics (MD) simulations to investigate the structural and dynamic effects of HRAS mutations. Our results showed that the stable model of HRAS had a significantly lower energy value of −18756 kj/mol compared to the initial model of −108915 kj/mol. The RMSD value for the wild-type complex was 4.40 Å, and the binding energies for the G60V, G60D, and D38H mutants were −107.09 kcal/mol, −109.42 kcal/mol, and −107.18 kcal/mol, respectively as compared to wild-type HRAS protein had −105.85 kcal/mol. The result of our investigation presents convincing corroboration for the potential functional significance of nsSNPs in augmenting HRAS expression and adding to the activation of malignant oncogenic signalling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Predicting the effects of rare genetic variants on oncogenic signaling pathways: A computational analysis of HRAS protein function

Ali¹,

Ali²,

Qamar³

et al. 2023

Front. Chem.

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“…So, the current study provides strong evidence that the selected nsSNPs might prompt deleterious effects as they have been computationally proven to alter the protein domains and motifs. They are also capable of changing structural conformations and interfering with drug binding 83 . Since these nsSNPs could have a damaging impact with respect to their protein structure, they might be used as potential genetic markers.…”

Section: Discussionmentioning

confidence: 99%

“…They are also capable of changing structural conformations and interfering with drug binding. 83 Since these nsSNPs could have a damaging impact with respect to their protein structure, they might be used as potential genetic markers.…”

Section: Discussionmentioning

confidence: 99%

Investigation of pathogenic germline variants in gastric cancer and development of “GasCanBase” database

Hossain,

Ahammad,

Moniruzzaman

et al. 2023

Cancer Reports

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BackgroundGastric cancer, which is also known as stomach cancer, can be influenced by both germline and somatic mutations. Non‐synonymous Single Nucleotide Polymorphisms (nsSNPs) in germline have long been reported to play a pivotal role in cancer progression.AimThe aim of this study is to examine the nsSNP in GC‐associated genes. The study also aims to develop a database with extensive information regarding the nsSNPs in the GC‐associated genes and their impacts.Methods and ResultsA total of 34,588 nsSNPs from 1,493,460 SNPs of the 40 genes were extracted from the available SNP database. Drug binding and energy minimization were examined by molecular docking and YASARA. To validate the existence of the germline CDH1 gene mutation (rs34466743) in the isolated blood DNA of gastric cancer (GC) patients, polymerase chain reaction (PCR) and DNA sequencing were performed. According to the results of the gene network analysis, 17 genes may interact with other types of cancer. A total of 11,363 nsSNPs were detected within the 40 GC genes. Among these, 474 nsSNPs were predicted to be damaging and 40 to be the most damaging. The SNPs in domain regions were thought to be strong candidates that alter protein functions. Our findings proposed that most of the selected nsSNPs were within the domains or motif regions. Free Energy Deviation calculation of protein structure pointed toward noteworthy changes in the structure of each protein that can demolish its natural function. Subsequently, drug binding confirmed the structural variation and the ineffectiveness of the drug against the mutant model in individuals with these germline variants. Furthermore, in vitro analysis of the rs34466743 germline variant from the CDH1 gene confirmed the strength and robustness of the pipeline that could expand the somatic alteration for causing cancer. In addition, a comprehensive gastric cancer polymorphism database named “GasCanBase” was developed to make data available to researchers.ConclusionThe findings of this study and the “GasCanBase” database may greatly contribute to our understanding of molecular epidemiology and the development of precise therapeutics for gastric cancer. GasCanBase is available at: https://www.gascanbase.com/.

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“…Moreover, studying the association between genetic variants and different disorders has received significant attention in recent years [13][14][15]. Given the extensive reporting and deposition of missense single-nucleotide polymorphisms (SNPs) in databases, it has become imperative to employ a filtration process to distinguish SNPs with potential pathogenicity from the larger pool of neutral variants [16,17].…”

Section: Introductionmentioning

confidence: 99%

Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy

Behairy,

Eid,

Otifi

et al. 2023

JPM

Self Cite

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Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms’ effects on function, stability, secondary structures, and 3D structure. The residues’ location on the protein domain and their conservation status were investigated as well. Moreover, docking tools along with structural biology were engaged in analyzing the SNPs’ effects on one of the developed IRAK4 inhibitors. By analyzing IRAK4 gene SNPs, the analysis distinguished ten variants as the most detrimental missense variants. All variants were situated in highly conserved positions on an important protein domain. L318S and L318F mutations were linked to changes in IRAK4 secondary structures. Eight SNPs were revealed to have a decreasing effect on the stability of IRAK4 via both I-Mutant 2.0 and Mu-Pro tools, while Mu-Pro tool identified a decreasing effect for the G198E SNP. In addition, detrimental effects on the 3D structure of IRAK4 were also discovered for the selected variants. Molecular modeling studies highlighted the detrimental impact of these identified SNP mutant residues on the druggability of the IRAK4 ATP-binding site towards the known target inhibitor, HG-12-6, as compared to the native protein. The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand–binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.

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Computational Analysis of Deleterious SNPs in NRAS to Assess Their Potential Correlation With Carcinogenesis

Cited by 7 publications

References 91 publications

Predicting the effects of rare genetic variants on oncogenic signaling pathways: A computational analysis of HRAS protein function

Predicting the effects of rare genetic variants on oncogenic signaling pathways: A computational analysis of HRAS protein function

Investigation of pathogenic germline variants in gastric cancer and development of “GasCanBase” database

Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy

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