了解NNAT基因翻译后乙酰化位点结构修饰的影响:预测其在神经性厌食症中的药物相互作用的计算机方法。

Muhammad Bilal Azmi, Areesha Jawed, Syed Danish Haseen Ahmed, Unaiza Naeem, Nazia Feroz, Arisha Saleem, Kainat Sardar, Shamim Akhtar Qureshi, M Kamran Azim
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In this regard, we investigated the PTM-acetylation site of the NNAT gene in terms of 19 other specific amino acid probabilities in place of wild type (WT) through various in silico algorithms. Based on the highest pathogenic impact computed through the consensus classifier tool, we generated 3 residue-specific (K59D, P, W) structurally modified 3D models of NNAT. These models were further tested through the AutoDock Vina tool to compute the molecular drug binding affinities and inhibition constant (Ki) of structural variants and WT 3D models.</p><p><strong>Results: </strong>With trained in silico machine learning algorithms and consensus classifier; the three structural modifications (K59D, P, W), which were also the most deleterious substitution at the acetylation site of the NNAT gene, showed the highest structural destabilization and decreased molecular flexibility. The validation and quality assessment of the 3D model of these structural modifications and WT were performed. 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引用次数: 0

摘要

目的:神经性厌食症(AN)是一种神经心理学公共卫生问题,具有社会致残的常规,影响一个人与食物的健康关系。神经蛋白(NNAT)基因在AN中的作用已经得到了很好的证实。蛋白质翻译后修饰(PTM)位点突变的影响只与蛋白质生化动力学的恶化有关。方法:为了了解基因型和表型之间的关系,有必要研究适当的生物学功能所需的蛋白质分子稳定性。在这方面,我们通过各种计算机算法研究了NNAT基因的ptm -乙酰化位点,以替代野生型(WT)的其他19种特定氨基酸概率。基于共识分类器计算出的最高致病影响,我们生成了3个残基特异性(K59D, P, W)的结构修饰的NNAT三维模型。通过AutoDock Vina工具进一步测试这些模型,计算结构变体的分子药物结合亲和力和抑制常数(Ki)以及WT 3D模型。结果:用训练好的计算机机器学习算法和共识分类器;三种结构修饰(K59D, P, W)也是NNAT基因乙酰化位点上最有害的取代,表现出最高的结构不稳定性和分子柔韧性降低。对这些结构修饰和WT的三维模型进行验证和质量评估。结果发现,与wt相比,结构修饰模型的ΔGbind (kcal/mol)值和抑制常数(Ki)相对较低。结论:NNAT基因的ptm -乙酰化位点由于可能的突变后果而发生的任何结构变化都将作为探索其与AN发病倾向关系的基础。证据水平:无证据水平——开放获取生物信息学研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Understanding the impact of structural modifications at the NNAT gene's post-translational acetylation site: in silico approach for predicting its drug-interaction role in anorexia nervosa.

Purpose: Anorexia nervosa (AN) is a neuropsychological public health concern with a socially disabling routine and affects a person's healthy relationship with food. The role of the NNAT (Neuronatin) gene in AN is well established. The impact of mutation at the protein's post-translational modification (PTM) site has been exclusively associated with the worsening of the protein's biochemical dynamics.

Methods: To understand the relationship between genotype and phenotype, it is essential to investigate the appropriate molecular stability of protein required for proper biological functioning. In this regard, we investigated the PTM-acetylation site of the NNAT gene in terms of 19 other specific amino acid probabilities in place of wild type (WT) through various in silico algorithms. Based on the highest pathogenic impact computed through the consensus classifier tool, we generated 3 residue-specific (K59D, P, W) structurally modified 3D models of NNAT. These models were further tested through the AutoDock Vina tool to compute the molecular drug binding affinities and inhibition constant (Ki) of structural variants and WT 3D models.

Results: With trained in silico machine learning algorithms and consensus classifier; the three structural modifications (K59D, P, W), which were also the most deleterious substitution at the acetylation site of the NNAT gene, showed the highest structural destabilization and decreased molecular flexibility. The validation and quality assessment of the 3D model of these structural modifications and WT were performed. They were further docked with drugs used to manage AN, it was found that the ΔGbind (kcal/mol) values and the inhibition constants (Ki) were relatively lower in structurally modified models as compared to WT.

Conclusion: We concluded that any future structural variation(s) at the PTM-acetylation site of the NNAT gene due to possible mutational consequences, will serve as a basis to explore its relationship with the propensity of developing AN.

Level of evidence: No level of evidence-open access bioinformatics research.

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来源期刊
CiteScore
6.50
自引率
10.30%
发文量
170
审稿时长
>12 weeks
期刊介绍: Eating and Weight Disorders - Studies on Anorexia, Bulimia and Obesity is a scientific journal whose main purpose is to create an international forum devoted to the several sectors of eating disorders and obesity and the significant relations between them. The journal publishes basic research, clinical and theoretical articles on eating disorders and weight-related problems: anorexia nervosa, bulimia nervosa, subthreshold eating disorders, obesity, atypical patterns of eating behaviour and body weight regulation in clinical and non-clinical populations.
期刊最新文献
Transcultural adaptation and validation of the Eating Self-Efficacy Brief Scale (ESEBS): the Brazilian version. The risk of kidney dysfunction in metabolically healthy/unhealthy population with normal weight or overweight/obesity: a systematic review and meta-analysis. Correction: Optimising healthcare transition of adolescents and young adults to adult care: a perspective statement of the Italian Society of Obesity. Multidimensional perfectionism and orthorexia: a systematic review and meta-analysis. Adverse childhood experiences and profiles of healthy orthorexia versus orthorexia nervosa: towards an explanatory model of orthorexia as a multidimensional eating style.
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