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
Abstract 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 m...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2023-11-01
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| Series: | Eating and Weight Disorders |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s40519-023-01618-4 |
| _version_ | 1797454082929065984 |
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| author | Muhammad Bilal Azmi Areesha Jawed Syed Danish Haseen Ahmed Unaiza Naeem Nazia Feroz Arisha Saleem Kainat Sardar Shamim Akhtar Qureshi M. Kamran Azim |
| author_facet | Muhammad Bilal Azmi Areesha Jawed Syed Danish Haseen Ahmed Unaiza Naeem Nazia Feroz Arisha Saleem Kainat Sardar Shamim Akhtar Qureshi M. Kamran Azim |
| author_sort | Muhammad Bilal Azmi |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T15:32:07Z |
| format | Article |
| id | doaj.art-6458fff759bb4037af07d33d3d3fec0c |
| institution | Directory Open Access Journal |
| issn | 1590-1262 |
| language | English |
| last_indexed | 2024-03-09T15:32:07Z |
| publishDate | 2023-11-01 |
| publisher | Springer |
| record_format | Article |
| series | Eating and Weight Disorders |
| spelling | doaj.art-6458fff759bb4037af07d33d3d3fec0c2023-11-26T12:09:33ZengSpringerEating and Weight Disorders1590-12622023-11-0128112010.1007/s40519-023-01618-4Understanding 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 nervosaMuhammad Bilal Azmi0Areesha Jawed1Syed Danish Haseen Ahmed2Unaiza Naeem3Nazia Feroz4Arisha Saleem5Kainat Sardar6Shamim Akhtar Qureshi7M. Kamran Azim8Department of Biochemistry, Dow Medical College, Dow University of Health SciencesDow Medical College, Dow University of Health SciencesDepartment of Biochemistry, Dow Medical College, Dow University of Health SciencesDow Medical College, Dow University of Health SciencesDepartment of Biochemistry, Dow Medical College, Dow University of Health SciencesDow Medical College, Dow University of Health SciencesDepartment of Biochemistry, University of KarachiDepartment of Biochemistry, University of KarachiDepartment of Biosciences, Mohammad Ali Jinnah UniversityAbstract 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.https://doi.org/10.1007/s40519-023-01618-4Anorexia nervosaAcetylationIn silicoNeuronatinPost-translational modification |
| spellingShingle | Muhammad Bilal Azmi Areesha Jawed Syed Danish Haseen Ahmed Unaiza Naeem Nazia Feroz Arisha Saleem Kainat Sardar Shamim Akhtar Qureshi M. Kamran Azim 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 Eating and Weight Disorders Anorexia nervosa Acetylation In silico Neuronatin Post-translational modification |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Anorexia nervosa Acetylation In silico Neuronatin Post-translational modification |
| url | https://doi.org/10.1007/s40519-023-01618-4 |
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