scholarly journals IntegratingIn SilicoPrediction Methods, Molecular Docking, and Molecular Dynamics Simulation to Predict the Impact of ALK Missense Mutations in Structural Perspective

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
C. George Priya Doss ◽  
Chiranjib Chakraborty ◽  
Luonan Chen ◽  
Hailong Zhu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
In Silico ◽  
Drug Response ◽  
Genomic Medicine ◽  
Dynamics Simulation ◽  
Missense Mutations ◽  
Anaplastic Lymphoma ◽  
The Impact

Over the past decade, advancements in next generation sequencing technology have placed personalized genomic medicine upon horizon. Understanding the likelihood of disease causing mutations in complex diseases as pathogenic or neutral remains as a major task and even impossible in the structural context because of its time consuming and expensive experiments. Among the various diseases causing mutations, single nucleotide polymorphisms (SNPs) play a vital role in defining individual’s susceptibility to disease and drug response. Understanding the genotype-phenotype relationship through SNPs is the first and most important step in drug research and development. Detailed understanding of the effect of SNPs on patient drug response is a key factor in the establishment of personalized medicine. In this paper, we represent a computational pipeline in anaplastic lymphoma kinase (ALK) for SNP-centred study by the application ofin silicoprediction methods, molecular docking, and molecular dynamics simulation approaches. Combination of computational methods provides a way in understanding the impact of deleterious mutations in altering the protein drug targets and eventually leading to variable patient’s drug response. We hope this rapid and cost effective pipeline will also serve as a bridge to connect the clinicians andin silicoresources in tailoring treatments to the patients’ specific genotype.

Prediction of Deleterious nsSNPs Causing CHARGE Syndrome Associated with the CHD7 Protein using Computational Approaches

2021 ◽  
Author(s):  
Nithya S. Rathinam ◽  
Madhana Priya N ◽  
Magesh Ramasamy
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Stability Analysis ◽  
Molecular Dynamics Simulation ◽  
Computational Methods ◽  
Catalytic Domain ◽  
Computational Prediction ◽  
Charge Syndrome ◽  
Dynamics Simulation ◽  
The Impact

Abstract The Chromo domain helicase DNA binding protein 7 (CHD7) is also known as ATP-dependent helicase CHD7, in humans, the CHD7 gene encodes it. Heterozygous mutations in this protein cause aggregation and has been determined to have an adverse role in causing CHARGE syndrome. Non-synonymous single nucleotide polymorphism (nsSNP) analysis tends to be deleterious of the protein yet to be employed with computational methods though being the highlight for novel investigations. Various computational methods were used to categorize the 201 identified nsSNPs in the catalytic domain of the CHD7 protein (the nsSNPs are observed to have a damaging effect in the catalytic domain). Pathogenicity analysis determined 81 nsSNPs to be pathogenic and further narrowed down to 61 nsSNPs by stability analysis. Based on the structure availability, the two nsSNPs (P2683S and R2702C) were selected and were checked in the computational tools for sequence analysis (pathogenicity analysis, stability analysis, physiochemical property analysis, and conservational analysis) and were determined to have a high impact over the protein molecule. The molecular dynamics simulation and principal component analysis (PCA) were performed to determine the conformational stability and flexibility change of the proteins. Subsequently, a molecular dynamic simulation (MDS) for 100ns was performed to understand the impact of the differences between the native and the mutant structures of the CHD7 protein. The simulation plots disclose very minute changes in patterns of stability, residue fluctuation, structure compactness, and flexibility regarding P2683S and R2702C mutation compared to the native structure. Further, Molecular docking was performed for the native and the mutant structures P2683S and R2702C to study the binding efficacy of the drugs Methyltestosterone and Estradiol resulting in a similar score with a very little difference to each other. The Native and mutants P2683S and R2702C have similar interaction of -5.7 kcal/mol, -5.9 kcal/mol and − 5.6 kcal/mol respectively with Methyltestosterone followed by a binding score of -6 kcal/mol, -5.6 kcal/mol and − 5.8 kcal/mol respectively for Estradiol. Detailed study about the disease, effect of nsSNP’s and the response of the drug towards the mutation are the key factors in order to launch a new personalized medicine. Therefore, in this study using various computational prediction methods, molecular dynamics simulation and molecular docking studies we have determined the nsSNP’s responsible to cause CHARGE syndrome and the drug response with respect to the determined nsSNP mutations. The outcomes acquired from our investigation will provide the data for experimental biologists for the additional procedure for examining the rest of the variations in CDH7 protein.

Cordycepin Downregulates Cdk-2 to Interfere with Cell Cycle and Increases Apoptosis by Generating ROS in Cervical Cancer Cells: in vitro and in silico Study

2019 ◽  
Vol 19 (2) ◽  
pp. 152-159 ◽  
Author(s):  
Mousumi Tania ◽  
Jakaria Shawon ◽  
Kazi Saif ◽  
Rudolf Kiefer ◽  
Mahdi Safaei Khorram ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Molecular Dynamics ◽  
Cervical Cancer ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Cancer Cells ◽  
In Silico ◽  
Dynamics Simulation ◽  
Cyclin E1 ◽  
Cervical Cancer Cells

Background: Cordycepin is a small molecule from medicinal mushroom Cordyceps, which has been reported for anticancer properties. </P><P> Objective: In this study, we have focused on the investigation of cordycepin effect on cervical cancer cells with further clarification of possible molecular mechanism. </P><P> Method: We have used cell viability and cell counting assay for cytotoxic effect of cordycepin, flow cytometric assay of apoptosis and cell cycle, and quantitative PCR (qPCR) and Western blotting for the determination of target gene expression. Molecular docking and Molecular dynamics simulation were used for in silico analysis of cordycepin affinity to target protein(s). </P><P> Results: Treatment of cordycepin controlled SiHa and HeLa cervical cancer cell growth, increased the rate of their apoptosis, and interfered with cell cycle, specifically elongated S-phase. qPCR results indicated that there was a downregulation of cell cycle proteins CDK-2, CYCLIN-A2 and CYCLIN-E1 in mRNA level by cordycepin treatment but no significant change was observed in pro-apoptotic or antiapoptotic proteins. The intracellular reactive oxygen species (ROS) level in cordycepin treated cells was increased significantly, implying that apoptosis might be induced by ROS. Western blot analysis confirmed significant decrease of Cdk-2 and mild decrease of Cyclin-E1 and Cyclin-A2 by cordycepin, which might be responsible for regulating cell cycle. Molecular docking indicated high binding affinity of cordycepin against Cdk-2. Molecular dynamics simulation further confirmed that the docked pose of cordycepin-Cdk-2 complex remained within the binding pocket for 10 ns. </P><P> Conclusion: Our study suggests that cordycepin is effective against cervical cancer cells, and regulating cell cycle via cell cycle proteins, especially downregulating Cdk-2, and inducing apoptosis by generating ROS are among the mechanisms of anticancer activities of cordycepin.

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