A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy

AbstractDRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd2 gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Despite numerous studies on the disease association of single nucleotide polymorphisms (SNPs) in the intronic regions, investigation into the coding regions is surprisingly limited. In this study, we aimed at identifying potential functionally and pharmaco-therapeutically deleterious non-synonymous SNPs of Drd2. A wide array of bioinformatics tools was used to evaluate the impact of nsSNPs on protein structure and functionality. Out of 260 nsSNPs retrieved from the dbSNP database, initially 9 were predicted as deleterious by 15 tools. Upon further assessment of their domain association, conservation profile, homology models and inter-atomic interaction, the mutant F389V was considered as the most impactful. In-depth analysis of F389V through Molecular Docking and Dynamics Simulation revealed a decline in affinity for its native agonist dopamine and an increase in affinity for the antipsychotic drug risperidone. Remarkable alterations in binding interactions and stability of the protein–ligand complex in simulated physiological conditions were also noted. These findings will improve our understanding of the consequence of nsSNPs in disease-susceptibility and therapeutic efficacy.

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A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy

10.1101/2021.06.11.448090 ◽

2021 ◽

Author(s):

Ishtiaque Ahammad ◽

Samia Sultana Lira

Keyword(s):

Neuronal Cell ◽

Surface Protein ◽

Dynamics Simulation ◽

Atomic Interaction ◽

Nucleotide Polymorphisms ◽

Drd2 Gene ◽

Ligand Complex ◽

Depth Analysis ◽

Dopamine Signaling ◽

The Impact

DRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd2 gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Despite numerous studies on the disease association of single nucleotide polymorphisms (SNPs) in the intronic regions, investigation into the coding regions is surprisingly limited. In this study, we aimed at identifying potential functionally and pharmaco-therapeutically deleterious non-synonymous SNPs of Drd2. A wide array of bioinformatics tools was used to evaluate the impact of nsSNPs on protein structure and functionality. Out of 260 nsSNPs retrieved from the dbSNP database, initially 9 were predicted as deleterious by 15 tools. Upon further assessment of their domain association, conservation profile, homology models and inter-atomic interaction, the mutant F389V was considered as the most impactful. In-depth analysis of F389V through Molecular Docking and Dynamics Simulation revealed a decline in affinity for its native agonist dopamine and an increase in affinity for the antipsychotic drug risperidone. Remarkable alterations in binding interactions and stability of the protein-ligand complex in simulated physiological conditions were also noted. These findings will improve our understanding of the consequence of nsSNPs in disease-susceptibility and therapeutic efficacy.

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THE IMPACT OF ESSENTIAL OILS OF THE LAMIACEAE FAMILY AGAINST TYLENCHULUS SEMIPENETRANS USING MOLECULAR MODELING METHODS

PLANT ARCHIVES ◽

10.51470/plantarchives.2021.v21.no1.270 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Bekkal Brikci S. ◽

Abdelli I. ◽

Hassani F. ◽

Bereksi Reguig M.

Keyword(s):

Essential Oils ◽

Control Method ◽

Acid Synthesis ◽

Dynamics Simulation ◽

Acetyl Coa Carboxylase ◽

Chemical Insecticide ◽

Ligand Complex ◽

Acetyl Coa ◽

Tylenchulus Semipenetrans ◽

The Impact

Tylenchulus semipenetrans is an economically important plant-parasitic nematode occurring in all citrus-producing regions of the world and causing a disease called “slow decline”. Chemical nematicides commonly used in agriculture have ecotoxicological effects. As a control method, attention has been paid to bio-nematicides that do not exhibit harmful effects on the ecosystem. In this study we will carry out the in scilico experiments in order to find the most coherent Enzyme-Ligand complex to lead to the best inhibitors of Acetyl CoA Carboxylase in Citrus Tylenchulus semipenetrans nematode. “Acetyl CoA Carboxylase” enzyme responsible for fatty acid synthesis in Tylenchulus semipenetrans, its alteration disrupting the synthesis of the surface layer, this inhibitory action is based on essential oils of aromatic plants, taking as an example the Lamiaceae family, using natural compounds extract from essential oils of Salvia verbenaca, Lavandula stoechas, Rosmarinus officinalis, and Thymus ciliatus. This study revealed for the first time that ?-phellandrène from Salvia verbenaca gives the best docking scores compared to Biotine, the co-crystallized inhibitor of the Acetyl CoA Carboxylase, to spirotetramat as chemical insecticide already used against citrus nematode, and to the other complexes. After that, the Molecular Dynamics Simulation study showed a good result for the ?-phellandrène- Acetyl CoA Carboxylase docked complex, for that we can consider that ?-phellandrène extracted from Salvia verbenaca’s essential oil as a functional inhibitor of Acetyl CoA Carboxylase activities and it can be used as good bio-nematicides against Tylenchulus semipenetrans.

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Insilico analysis of structural and functional impact of SNPs in Pleckstrin

10.1101/782623 ◽

2019 ◽

Author(s):

Arpit Kumar Pradhan ◽

Ashwin Jainarayanan ◽

M. A. Nithishwer ◽

Shyamasree Ghosh

Keyword(s):

Molecular Evolution ◽

Inflammatory Diseases ◽

Aortic Aneurysms ◽

Nucleotide Polymorphisms ◽

Over Expression ◽

Abdominal Aortic ◽

Obstructive Sleep ◽

Potential Structure ◽

And Function ◽

The Impact

AbstractPleckstrin (PLEK) gene has been associated with a variety of disorders including autoimmune, inflammatory diseases and cancer. Mutation in this gene has been reported to be associated with autoimmune celiac disease (CD), increased atrophy in multiple sclerosis (MS), obstructive sleep apnea (OSA), abdominal aortic aneurysms, over expression in inflammatory disorders including periodontis, risk for ependymoma relapse, bladder cancer, melanoma, lung, and colorectal cancer revealing the importance of study of the PLEK. PLEK gene has been reported from other animals and therefore we have studied the molecular evolution of the PLEK gene by insilico approaches. Single nucleotide polymorphisms (SNPs), in humans have been reported to cause potential structure-function alteration in proteins. In this study we have tried to understand by insilico approaches the (i) molecular evolution of PLEK and (ii) the impact of potentially deleterious single non-synonymous SNPs (nsSNPs) on the structure and function of Pleckstrin protein. We report for the first time using molecular dynamic simulation (MDS), the impact of SNPrs17035364 and rs3816281 on the structural alterations of Pleckstrin with implications in altering its biological function which may find importance as diagnostic markers.

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Neuroimmunoendocrine Regulation of the Prion Protein in Neutrophils

Journal of Biological Chemistry ◽

10.1074/jbc.m112.394924 ◽

2012 ◽

Vol 287 (42) ◽

pp. 35506-35515 ◽

Cited By ~ 21

Author(s):

Rafael M. Mariante ◽

Alberto Nóbrega ◽

Rodrigo A. P. Martins ◽

Rômulo B. Areal ◽

Maria Bellio ◽

...

Keyword(s):

Prion Protein ◽

Surface Protein ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathies ◽

Systemic Injection ◽

A Cell ◽

And Function ◽

Acute And Chronic Inflammation ◽

The Impact

The prion protein (PrPC) is a cell surface protein expressed mainly in the nervous system. In addition to the role of its abnormal conformer in transmissible spongiform encephalopathies, normal PrPC may be implicated in other degenerative conditions often associated with inflammation. PrPC is also present in cells of hematopoietic origin, including T cells, dendritic cells, and macrophages, and it has been shown to modulate their functions. Here, we investigated the impact of inflammation and stress on the expression and function of PrPC in neutrophils, a cell type critically involved in both acute and chronic inflammation. We found that systemic injection of LPS induced transcription and translation of PrPC in mouse neutrophils. Up-regulation of PrPC was dependent on the serum content of TGF-β and glucocorticoids (GC), which, in turn, are contingent on the activation of the hypothalamic-pituitary-adrenal axis in response to systemic inflammation. GC and TGF-β, either alone or in combination, directly up-regulated PrPC in neutrophils, and accordingly, the blockade of GC receptors in vivo curtailed the LPS-induced increase in the content of PrPC. Moreover, GC also mediated up-regulation of PrPC in neutrophils following noninflammatory restraint stress. Finally, neutrophils with up-regulated PrPC presented enhanced peroxide-dependent cytotoxicity to endothelial cells. The data demonstrate a novel interplay of the nervous, endocrine, and immune systems upon both the expression and function of PrPC in neutrophils, which may have a broad impact upon the physiology and pathology of various organs and systems.

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Computational Screening and Analysis of Lung Cancer Related Non-Synonymous Single Nucleotide Polymorphisms on the Human Kirsten Rat Sarcoma Gene

Molecules ◽

10.3390/molecules24101951 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1951 ◽

Cited By ~ 4

Author(s):

Qiankun Wang ◽

Aamir Mehmood ◽

Heng Wang ◽

Qin Xu ◽

Yi Xiong ◽

...

Keyword(s):

Lung Cancer ◽

Single Nucleotide Polymorphisms ◽

Dynamics Simulation ◽

Nucleotide Polymorphisms ◽

Kras Gene ◽

Kras Mutations ◽

Single Nucleotide ◽

Mutant Proteins ◽

Computational Screening ◽

The Impact

The human KRAS (Kirsten rat sarcoma) is an oncogene, involved in the regulation of cell growth and division. The mutations in the KRAS gene have the potential to cause normal cells to become cancerous in human lungs. In the present study, we focus on non-synonymous single nucleotide polymorphisms (nsSNPs), which are point mutations in the DNA sequence leading to the amino acid variants in the encoded protein. To begin with, we developed a pipeline to utilize a set of computational tools in order to obtain the most deleterious nsSNPs (Q22K, Q61P, and Q61R) associated with lung cancer in the human KRAS gene. Furthermore, molecular dynamics simulation and structural analyses of the 3D structures of native and mutant proteins confirmed the impact of these nsSNPs on the stability of the protein. Finally, the experimental results demonstrated that the structural stability of the mutant proteins was worse than that of the native protein. This study provides significant guidance for narrowing down the number of KRAS mutations to be screened as potential diagnostic biomarkers and to better understand the structural and functional mechanisms of the KRAS protein.

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Prediction of Deleterious Non-synonymous SNPs of Human STK11 Gene by Combining Algorithms, Molecular Docking, and Molecular Dynamics Simulation

Scientific Reports ◽

10.1038/s41598-019-52308-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 10

Author(s):

Md. Jahirul Islam ◽

Akib Mahmud Khan ◽

Md. Rimon Parves ◽

Md Nayeem Hossain ◽

Mohammad A. Halim

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Protein Structures ◽

Catalytic Efficiency ◽

Suppressor Gene ◽

Kinase Domain ◽

Dynamics Simulation ◽

Nucleotide Polymorphisms ◽

Stk11 Gene ◽

The Impact

Abstract Serine-threonine kinase11 (STK11) is a tumor suppressor gene which plays a key role in regulating cell growth and apoptosis. It is widely known as a multitasking kinase and engaged in cell polarity, cell cycle arrest, chromatin remodeling, energy metabolism, and Wnt signaling. The substitutions of single amino acids in highly conserved regions of the STK11 protein are associated with Peutz–Jeghers syndrome (PJS), which is an autosomal dominant inherited disorder. The abnormal function of the STK11 protein is still not well understood. In this study, we classified disease susceptible single nucleotide polymorphisms (SNPs) in STK11 by using different computational algorithms. We identified the deleterious nsSNPs, constructed mutant protein structures, and evaluated the impact of mutation by employing molecular docking and molecular dynamics analysis. Our results show that W239R and W308C variants are likely to be highly deleterious mutations found in the catalytic kinase domain, which may destabilize structure and disrupt the activation of the STK11 protein as well as reduce its catalytic efficiency. The W239R mutant is likely to have a greater impact on destabilizing the protein structure compared to the W308C mutant. In conclusion, these mutants can help to further realize the large pool of disease susceptibilities linked with catalytic kinase domain activation of STK11 and assist to develop an effective drug for associated diseases.

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Investigating Variations/SNPs in AUH Gene Causing 3-Methylglutaconic Aciduria, Type I

International Journal of Applied Research in Bioinformatics ◽

10.4018/ijarb.2022010104 ◽

2022 ◽

Vol 12 (1) ◽

pp. 1-13

Author(s):

Malik Muhammad Sajjad ◽

Sarah Bukhari ◽

Omer Aziz

Keyword(s):

Structure And Function ◽

Genomic Variation ◽

Type I ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

A Genome ◽

Project Hope ◽

And Function ◽

The Impact ◽

Methylglutaconic Aciduria

A Single nucleotide polymorphisms (SNPs) is a source variation in a genome. The AUH gene gives guidance about how to generate an enzyme named 3-methylglutaconyl-CoA hydratase. Mutations in AUH gene leads to 3-Methylglutaconic aciduria type I disease. The authors used multiple bioinformatics tools SIFT, Provean, PolyPhen, PHD-SNP, I-Mutant, ConSurf server and Project HOPE to isolate missense SNPs that should be deleterious to the structure and function of the AUH protein. This research aims to analyze the impact of missense SNPs on the structure and function of AUH protein. There have been a total of 259 Missense SNPs obtained, of which 13 mutations were identified as deleterious to the structure and function of the AUH protein. This is the first study in relation to AUH gene missense SNPs where most damaging SNPs associated with the AUH gene were examined using computational analysis. This research could be useful in designing specific medicines for treatment of genomic variation diseases.

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Computational and Molecular Dynamics Simulation Approach To Analyze the Impact of XPD Gene Mutation on Protein Stability and Function

10.1101/2020.07.18.209841 ◽

2020 ◽

Author(s):

Nagesh Kishan Panchal ◽

Aishwarya Bhale ◽

Vinod Kumar Verma ◽

Syed Sultan Beevi

Keyword(s):

Dna Repair ◽

Protein Stability ◽

Double Helix ◽

Dynamics Simulation ◽

Missense Mutations ◽

Simulated Environment ◽

Dna Repair Deficiency ◽

And Function ◽

The Impact ◽

Damaged Dna

AbstractXPD acts as a functional helicase and aids in unwinding double helix around damaged DNA, leading to efficient DNA repair. Mutations of XPD give rise to DNA-repair deficiency diseases and cancer proneness. In this study, cancer-causing missense mutation that could inactivate helicase function and hinder its binding with other complexes were analysed using bioinformatics approach. Rigorous computational methods were employed to understand the molecular pathogenic profile of mutation. The mutant model with the desired mutation was built with I-TASSER. GROMACS 5.0.1 was used to evaluate the effect of a mutation on protein stability and function. Of the 276 missense mutations, 64 were found to be disease-causing. Out of these 64, seven were of cancer-causing mutations. Among these, we evaluated K48R mutation in a computational simulated environment to determine its impact on protein stability and function since K48 position was ascertained to be highly conserved and substitution with arginine could impair the XPD activity. Molecular Dynamic Simulation and Essential Dynamics analysis showed that K48R mutation altered protein structural stability and produced conformational drift. Our predictions thus revealed that K48R mutation could impair the XPD helicase activity and affect its ability to repair the damaged DNA, thus augmenting the risk for cancer.

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Microtubule dynamics in cytoskeleton, neurodegenerative and psychiatric disease

STEMedicine ◽

10.37175/stemedicine.v2i6.81 ◽

2021 ◽

Vol 2 (6) ◽

pp. e81

Author(s):

Simone Mortal

Keyword(s):

Neurodegenerative Diseases ◽

Structural Integrity ◽

Neuronal Cell ◽

Psychiatric Disease ◽

Psychiatric Illnesses ◽

Associated Proteins ◽

Dynamics And Function ◽

And Function ◽

The Impact ◽

Β Tubulin

Microtubules (MTs) are fundamental polymers composed by α and β tubulin, they provide integrity to neuronal cell and are necessaries in intracellular trafficking and organization. The extension and retraction of MTs occur with the addition or removal of α and β tubulin subunits and the binding with microtubule associated proteins (MAPs) that selectively target specific tubulin regions, manipulating the MT dynamics and function. Altered MT homeostasis can compromise the function of MTs in the structural integrity and axonal transport inside the neuron. Here I review the evidence of MT anomalies in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis and traumatic brain injury and psychiatric disorders, such as depression, schizophrenia, and bipolar disorder. The focus of this review is to point out which can be the impact of MT issues in the major neurodegenerative diseases and discuss which MT abnormalities can lead to psychiatric illnesses.

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Mutational Landscape of Pirin and Elucidation of the Impact of Most Detrimental Missense Variants That Accelerate the Breast Cancer Pathways: A Computational Modelling Study

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.692835 ◽

2021 ◽

Vol 8 ◽

Author(s):

Muhammad Suleman ◽

Muhammad Tahir ul Qamar ◽

Shoaib Saleem ◽

Sajjad Ahmad ◽

Syed Shujait Ali ◽

...

Keyword(s):

Breast Cancer ◽

Protein Structure ◽

Computational Modelling ◽

Tumor Formation ◽

Transcriptional Level ◽

Nucleotide Polymorphisms ◽

Cancer Pathways ◽

Eukaryotic Organisms ◽

And Function ◽

The Impact

Pirin (PIR) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, it has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level. Keeping in view the importance of PIR in many crucial cellular processes in humans, we used a variety of computational tools to identify non-synonymous single-nucleotide polymorphisms (SNPs) in the PIR gene that are highly deleterious for the structure and function of PIR protein. Out of 173 SNPs identified in the protein, 119 are non-synonymous, and by consensus, 24 mutations were confirmed to be deleterious in nature. Mutations such as V257A, I28T, and I264S were unveiled as highly destabilizing due to a significant stability fold change on the protein structure. This observation was further established through molecular dynamics (MD) simulation that demonstrated the role of the mutation in protein structure destability and affecting its internal dynamics. The findings of this study are believed to open doors to investigate the biological relevance of the mutations and drugability potential of the protein.

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