Computational algorithmic and molecular dynamics study of functional and structural impacts of non-synonymous single nucleotide polymorphisms in human DHFR gene

Alam, Md. Shahed; Saleh, Md. Abu; Mozibullah, Md.; Riham, Ashik Tanvir; Solayman, Md.; Gan, Siew Hua

doi:10.1016/j.compbiolchem.2021.107587

Cited by 3 publications

(3 citation statements)

References 69 publications

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“…A wide range of algorithmic tools that operate on different methodologies were employed to predict the functional impacts and disease‐associated missense variants with high accuracy and reliability [ 18 , 24 ]. All the employed algorithmic tools in our study were divided into two categories that are functional impact and pathogenicity prediction tools.…”

Section: Methodsmentioning

confidence: 99%

Identifying Oncogenic Missense Single Nucleotide Polymorphisms in Human SAT1 Gene Using Computational Algorithms and Molecular Dynamics Tools

Mozibullah,

Khatun,

Sikder

et al. 2024

Cancer Reports

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BackgroundThe human SAT1 gene encodes spermidine/spermine N1‐acetyltransferase 1 (SSAT1), a regulatory biological catalyst of polyamine catabolism. Numerous essential biological processes, such as cellular proliferation, differentiation, and survival, depend on polyamines like spermidine and spermine. Thus, SSAT1 is involved in key cellular activities such as proliferation and survival of cells and mediates various diseases including cancer. A plethora of studies established the involvement of missense single nucleotide polymorphisms (SNPs) in numerous pathological conditions due to their ability to adversely affect the structure and subsequent function of the protein.AimsTo date, an in silico study to identify the pathogenic missense SNPs of the human SAT1 gene has not been accomplished yet. This study aimed to filter the missense SNPs that were functionally detrimental and pathogenic.Methods and ResultsThe rs757435207 (I21N) was ascertained to be the most deleterious and pathogenic by all algorithmic tools. Stability and evolutionary conservation analysis tools also stated that I21N variant decreased the stability and was located in the highly conserved residue. Molecular dynamics simulation revealed that I21N caused substantial alterations in the conformational stability and dynamics of the SSAT1 protein. Consequently, the I21N variant could disrupt the native functional roles of the SSAT1 enzyme.ConclusionTherefore, the I21N variant was identified and concluded to be an oncogenic missense variant of the human SAT1 gene. Overall, the findings of this study would be a great directory of future experimental research to develop personalized medicine.

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Section: Methodsmentioning

confidence: 99%

Identifying Oncogenic Missense Single Nucleotide Polymorphisms in Human SAT1 Gene Using Computational Algorithms and Molecular Dynamics Tools

Mozibullah,

Khatun,

Sikder

et al. 2024

Cancer Reports

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“…This study from the eastern part of India evaluating the genetic defects in folate metabolism pathway genes specified that “rs1801133” was linked with NTDs in patients and can act as a molecular marker for estimating the vulnerability of NTDs 26 . Three of the 12 most deleterious nsSNPs of the DHFR gene R71T, G118D, and Y122D were found in the cofactor and ligand binding active regions 27 . Variants of SHMT2 and DMGDH have been associated with neural tube abnormalities 8 .…”

Section: Folate Metabolism: Genes and Associated Diseasesmentioning

confidence: 99%

“…26 Three of the 12 most deleterious nsSNPs of the DHFR gene R71T, G118D, and Y122D were found in the cofactor and ligand binding active regions. 27 Variants of SHMT2 and DMGDH have been associated with neural tube abnormalities. 8 ATIC, SHMT2, and SLC46A1 have critical roles in one-carbon (1-C) transfer.…”

Section: Folate Metabolism: Genes and Associated Diseasesmentioning

confidence: 99%

One carbon metabolism and its implication in health and immune functions

Dang,

Jain,

Dhanda

et al. 2024

Cell Biochemistry & Function

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One carbon (1C) metabolism is critical for cellular viability and physiological homeostasis. Starting from its crucial involvement in purine biosynthesis to posttranslational modification of proteins, 1C metabolism contributes significantly to the development and cellular differentiation through methionine and folate cycles that are pivotal for cellular function. Genetic polymorphisms of several genes of these pathways are implicated in disease pathogenesis and drug metabolism. Metabolic products of 1C metabolism have significant roles in epigenetic modifications through DNA and histone protein methylation. Homocysteine is a product that has clinical significance in the diagnosis and prognosis of several critical illnesses, including chronic immune diseases and cancers. Regulation of the function and differentiation of immune cells, including T‐cells, B‐cells, macrophages, and so forth, are directly influenced by 1C metabolism and thus have direct implications in several immune disease biology. Recent research on therapeutic approaches is targeting nuclear, cytoplasmic, and mitochondrial 1C metabolism to manage and treat metabolic (i.e., type 2 diabetes), neurodegenerative (i.e., Alzheimer's disease), or immune (i.e., rheumatoid arthritis) diseases. 1C metabolism is being explored for therapeutic intervention as a common determinant for a spectrum of immune and metabolic diseases. Identifying the association or correlation between essential metabolic products of this pathway and disease onset or prognosis would further facilitate the clinical monitoring of diseases.

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Dihydrofolate Reductase (DHFR) Inhibitors: A Comprehensive Review

Sehrawat

Rathee

Khatkar³

et al. 2024

CMC

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Background: Dihydrofolate reductase (DHFR) is an indispensable enzyme required for the survival of most prokaryotic and eukaryotic cells as it is involved in the biosynthesis of essential cellular components. DHFR has attracted a lot of attention as a molecular target for various diseases like cancer, bacterial infection, malaria, tuberculosis, dental caries, trypanosomiasis, leishmaniasis, fungal infection, influenza, Buruli ulcer, and respiratory illness. Various teams of researchers have reported different DHFR inhibitors to explore their therapeutic efficacy. Despite all the progress made, there is a strong need to find more novel leading structures, which may be used as better and safe DHFR inhibitors, especially against the microorganisms which are resistant to the developed drug candidates. Objective: This review aims to pay attention to recent development, particularly made in the past two decades and published in this field, and pay particular attention to promising DHFR inhibitors. Hence, an attempt has been made in this article to highlight the structure of dihydrofolate reductase, the mechanism of action of DHFR inhibitors, most recently reported DHFR inhibitors, diverse pharmacological applications of DHFR inhibitors, reported in-silico study data and recent patents based on DHFR inhibitors to comprehensively portray the current scenery for researchers interested in designing novel DHFR inhibitors. Conclusion: A critical review of recent studies revealed that most novel DHFR inhibitor compounds either synthetically or naturally derived are characterized by the presence of heterocyclic moieties in their structure. Non-classical antifolates like trimethoprim, pyrimethamine, and proguanil are considered excellent templates to design novel DHFR inhibitors, and most of them have substituted 2,4-diamino pyrimidine motifs. Targeting DHFR has massive potential to be investigated for newer therapeutic possibilities to treat various diseases of clinical importance.

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Computational algorithmic and molecular dynamics study of functional and structural impacts of non-synonymous single nucleotide polymorphisms in human DHFR gene

Cited by 3 publications

References 69 publications

Identifying Oncogenic Missense Single Nucleotide Polymorphisms in Human SAT1 Gene Using Computational Algorithms and Molecular Dynamics Tools

Identifying Oncogenic Missense Single Nucleotide Polymorphisms in Human SAT1 Gene Using Computational Algorithms and Molecular Dynamics Tools

One carbon metabolism and its implication in health and immune functions

Dihydrofolate Reductase (DHFR) Inhibitors: A Comprehensive Review

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