Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches
Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular...
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MDPI AG
2021-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/8/1104 |
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| author | Rafal Madaj Bartlomiej Gostynski Roza Pawlowska Arkadiusz Chworos |
| author_facet | Rafal Madaj Bartlomiej Gostynski Roza Pawlowska Arkadiusz Chworos |
| author_sort | Rafal Madaj |
| collection | DOAJ |
| description | Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of β,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties. |
| first_indexed | 2024-03-10T08:59:26Z |
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| id | doaj.art-68e51727bd734e97bb098eae234b76d6 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T08:59:26Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-68e51727bd734e97bb098eae234b76d62023-11-22T06:54:52ZengMDPI AGBiomolecules2218-273X2021-07-01118110410.3390/biom11081104Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics ApproachesRafal Madaj0Bartlomiej Gostynski1Roza Pawlowska2Arkadiusz Chworos3Division of Bioorganic Chemistry Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza, 112, 90-363 Lodz, PolandDivision of Bioorganic Chemistry Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza, 112, 90-363 Lodz, PolandDivision of Bioorganic Chemistry Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza, 112, 90-363 Lodz, PolandDivision of Bioorganic Chemistry Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza, 112, 90-363 Lodz, PolandTissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of β,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties.https://www.mdpi.com/2218-273X/11/8/1104TNAPalkaline phosphatasenucleotide analoguesbisphosphonate derivativesmolecular dockingmolecular dynamics |
| spellingShingle | Rafal Madaj Bartlomiej Gostynski Roza Pawlowska Arkadiusz Chworos Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches Biomolecules TNAP alkaline phosphatase nucleotide analogues bisphosphonate derivatives molecular docking molecular dynamics |
| title | Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches |
| title_full | Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches |
| title_fullStr | Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches |
| title_full_unstemmed | Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches |
| title_short | Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches |
| title_sort | tissue nonspecific alkaline phosphatase tnap as the enzyme involved in the degradation of nucleotide analogues in the ligand docking and molecular dynamics approaches |
| topic | TNAP alkaline phosphatase nucleotide analogues bisphosphonate derivatives molecular docking molecular dynamics |
| url | https://www.mdpi.com/2218-273X/11/8/1104 |
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