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

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.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samia Sultana Lira ◽  
Ishtiaque Ahammad
Keyword(s):  
Neuronal Cell ◽  
Surface Protein ◽  
Dynamics Simulation ◽  
Atomic Interaction ◽  
Nucleotide Polymorphisms ◽  
Ligand Complex ◽  
Depth Analysis ◽  
Dopamine Signaling ◽  
And Function ◽  
The Impact

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.

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

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.

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

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1951 ◽  
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.

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

2019 ◽  
Vol 9 (1) ◽  
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.

Emerging Proof of Protein Misfolding and Interactions in Multifactorial Alzheimer's Disease

2020 ◽  
Vol 20 (26) ◽  
pp. 2380-2390 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Abdullah Al Mamun ◽  
Md. Ataur Rahman ◽  
Tapan Behl ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Misfolded Proteins ◽  
Cell Organelles ◽  
The Impact

Objective: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, characterized by the extracellular accumulations of amyloid beta (Aβ) as senile plaques and intracellular aggregations of tau in the form of neurofibrillary tangles (NFTs) in specific brain regions. In this review, we focus on the interaction of Aβ and tau with cytosolic proteins and several cell organelles as well as associated neurotoxicity in AD. Summary: Misfolded proteins present in cells accompanied by correctly folded, intermediately folded, as well as unfolded species. Misfolded proteins can be degraded or refolded properly with the aid of chaperone proteins, which are playing a pivotal role in protein folding, trafficking as well as intermediate stabilization in healthy cells. The continuous aggregation of misfolded proteins in the absence of their proper clearance could result in amyloid disease including AD. The neuropathological changes of AD brain include the atypical cellular accumulation of misfolded proteins as well as the loss of neurons and synapses in the cerebral cortex and certain subcortical regions. The mechanism of neurodegeneration in AD that leads to severe neuronal cell death and memory dysfunctions is not completely understood until now. Conclusion: Examining the impact, as well as the consequences of protein misfolding, could help to uncover the molecular etiologies behind the complicated AD pathogenesis.

The Catholic Diaspora—Experiences of Evacuation

2018 ◽  
Author(s):  
Thomas Brodie
Keyword(s):  
Urban Areas ◽  
Religious Practice ◽  
Catholic Clergy ◽  
Profound Influence ◽  
The Social ◽  
Depth Analysis ◽  
Nazi Era ◽  
Mass Evacuation ◽  
The Impact ◽  
Pastoral Practice

This chapter analyses the impact exerted on the Catholic Church’s pastoral networks in Germany by the mass evacuation of laypeople from bombed urban areas as of 1941. Drawing on the voluminous correspondence of priests and curates despatched from the Rhineland and Westphalia to Saxony, Thuringia, Silesia, Austria, and elsewhere to minister to Catholic evacuees, this chapter provides in-depth analysis of the social and cultural histories of religious practice in wartime Germany. It demonstrates that the evacuation of laypeople—a topic long neglected within histories of wartime religious practice—exerted a profound influence on pastoral practice by the years 1943–5, placing unprecedented pressures on the Catholic clergy of the dioceses central to this study (Aachen, Cologne and Münster). This chapter therefore also casts new light on regionalism in Germany during the Nazi era.

Impact Load Buffering Method Based on Stress Wave Attenuation Principle

2019 ◽  
Vol 11 (02) ◽  
pp. 1950019 ◽  
Author(s):  
Lin Gan ◽  
He Zhang ◽  
Cheng Zhou ◽  
Lin Liu
Keyword(s):  
Stress Wave ◽  
Wave Attenuation ◽  
Impact Load ◽  
Dynamics Simulation ◽  
Scanning System ◽  
Isolation Method ◽  
Element Analysis ◽  
System A ◽  
High Emission ◽  
The Impact

Rotating scanning motor is the important component of synchronous scanning laser fuze. High emission overload environment in the conventional ammunition has a serious impact on the reliability of the motor. Based on the theory that the buffer pad can attenuate the impact stress wave, a new motor buffering Isolation Method is proposed. The dynamical model of the new buffering isolation structure is established by ANSYS infinite element analysis software to do the nonlinear impact dynamics simulation of rotating scanning motor. The effectiveness of Buffering Isolation using different materials is comparatively analyzed. Finally, the Macht hammer impact experiment is done, the results show that in the experience of the 70,000[Formula: see text]g impact acceleration, the new buffering Isolation method can reduce the impact load about 15 times, which can effectively alleviate the plastic deformation of rotational scanning motor and improve the reliability of synchronization scanning system. A new method and theoretical basis of anti-high overload research for Laser Fuze is presented.

scholarly journals The Impact of the Electric Field on Surface Condensation of Water Vapor: Insight from Molecular Dynamics Simulation

Nanomaterials ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 64 ◽  
Author(s):  
Qin Wang ◽  
Hui Xie ◽  
Zhiming Hu ◽  
Chao Liu
Keyword(s):  
Molecular Dynamics ◽  
Water Vapor ◽  
Electric Field ◽  
Intermolecular Forces ◽  
Dynamics Simulation ◽  
Water Molecules ◽  
Attraction Force ◽  
Condensation Rate ◽  
Shape Transformation ◽  
The Impact

In this study, molecular dynamics simulations were carried out to study the coupling effect of electric field strength and surface wettability on the condensation process of water vapor. Our results show that an electric field can rotate water molecules upward and restrict condensation. Formed clusters are stretched to become columns above the threshold strength of the field, causing the condensation rate to drop quickly. The enhancement of surface attraction force boosts the rearrangement of water molecules adjacent to the surface and exaggerates the threshold value for shape transformation. In addition, the contact area between clusters and the surface increases with increasing amounts of surface attraction force, which raises the condensation efficiency. Thus, the condensation rate of water vapor on a surface under an electric field is determined by competition between intermolecular forces from the electric field and the surface.

scholarly journals Impact of PD-1 gene polymorphism and its interaction with tea drinking on susceptibility to tuberculosis

2021 ◽  
Vol 149 ◽  
Author(s):  
Jing Wang ◽  
Mian Wang ◽  
Zihao Li ◽  
Xinyin Wu ◽  
Xian Zhang ◽  
...  
Keyword(s):  
Case Control Study ◽  
Preventive Measures ◽  
Nucleotide Polymorphisms ◽  
Unconditional Logistic Regression ◽  
Negative Interaction ◽  
Single Nucleotide ◽  
High Risk Populations ◽  
Tea Drinking ◽  
The Impact ◽  
Control Study

Abstract The aim of this study was to explore the impact of polymorphism of PD-1 gene and its interaction with tea drinking on susceptibility to tuberculosis (TB). A total of 503 patients with TB and 494 controls were enrolled in this case–control study. Three single-nucleotide polymorphisms of PD-1 (rs7568402, rs2227982 and rs36084323) were genotyped and unconditional logistic regression analysis was used to identify the association between PD-1 polymorphism and TB, while marginal structural linear odds models were used to estimate the interactions. Genotypes GA (OR 1.434), AA (OR 1.891) and GA + AA (OR 1.493) at rs7568402 were more prevalent in the TB patients than in the controls (P < 0.05). The relative excess risk of interaction (RERI) between rs7568402 of PD-1 genes and tea drinking was −0.3856 (95% confidence interval −0.7920 to −0.0209, P < 0.05), which showed a negative interaction. However, the RERIs between tea drinking and both rs2227982 and rs36084323 of PD-1 genes were not statistically significant. Our data demonstrate that rs7568402 of PD-1 genes was associated with susceptibility to TB, and there was a significant negative interaction between rs7568402 and tea drinking. Therefore, preventive measures through promoting the consumption of tea should be emphasised in the high-risk populations.

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