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Identification of Novel Tau-Tubulin Kinase 2 Inhibitors Using Computational Approaches
[Image: see text] Tau tubulin kinase 2 (TTBK2) associated with multiple diseases is one of the kinases which phosphorylates tau and tubulin. Numerous efforts have been made to understand the role of TTBK2 in protein folding mechanisms and misfolding behavior. The misfolded protein intermediates form...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099139/ https://www.ncbi.nlm.nih.gov/pubmed/37065061 http://dx.doi.org/10.1021/acsomega.3c00225 |
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author | Ahamad, Shahzaib Hema, Kanipakam Gupta, Dinesh |
author_facet | Ahamad, Shahzaib Hema, Kanipakam Gupta, Dinesh |
author_sort | Ahamad, Shahzaib |
collection | PubMed |
description | [Image: see text] Tau tubulin kinase 2 (TTBK2) associated with multiple diseases is one of the kinases which phosphorylates tau and tubulin. Numerous efforts have been made to understand the role of TTBK2 in protein folding mechanisms and misfolding behavior. The misfolded protein intermediates form polymers with unwanted aggregation properties that initiate several diseases, including Alzheimer’s. The availability of TTBK2 inhibitors can enhance the understanding of the molecular mechanism of action of the kinase and assist in developing novel therapeutics. In the quest for TTBK2 inhibitors, this study focuses on screening two chemical libraries (ChEMBL and ZINC-FDA). The molecular docking, RO5/absorption, distribution, metabolism, and excretion/toxicity, density functional theory, molecular dynamics (MD) simulations, and molecular mechanics with generalized Born and surface area solvation techniques enabled shortlisting of the four most active compounds, namely, ChEMBL1236395, ChEMBL2104398, ChEMBL3427435, and ZINC000000509440. Moreover, 500 ns MD simulation was performed for each complex, which provided valuable insights into the structural changes in the complexes. The relative fluctuation, solvent accessible surface area, atomic gyration, compactness covariance, and free energy landscapes revealed that the compounds could stabilize the TTBK2 protein. Overall, this study would be valuable for the researchers targeting the development of novel TTBK2 inhibitors. |
format | Online Article Text |
id | pubmed-10099139 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-100991392023-04-14 Identification of Novel Tau-Tubulin Kinase 2 Inhibitors Using Computational Approaches Ahamad, Shahzaib Hema, Kanipakam Gupta, Dinesh ACS Omega [Image: see text] Tau tubulin kinase 2 (TTBK2) associated with multiple diseases is one of the kinases which phosphorylates tau and tubulin. Numerous efforts have been made to understand the role of TTBK2 in protein folding mechanisms and misfolding behavior. The misfolded protein intermediates form polymers with unwanted aggregation properties that initiate several diseases, including Alzheimer’s. The availability of TTBK2 inhibitors can enhance the understanding of the molecular mechanism of action of the kinase and assist in developing novel therapeutics. In the quest for TTBK2 inhibitors, this study focuses on screening two chemical libraries (ChEMBL and ZINC-FDA). The molecular docking, RO5/absorption, distribution, metabolism, and excretion/toxicity, density functional theory, molecular dynamics (MD) simulations, and molecular mechanics with generalized Born and surface area solvation techniques enabled shortlisting of the four most active compounds, namely, ChEMBL1236395, ChEMBL2104398, ChEMBL3427435, and ZINC000000509440. Moreover, 500 ns MD simulation was performed for each complex, which provided valuable insights into the structural changes in the complexes. The relative fluctuation, solvent accessible surface area, atomic gyration, compactness covariance, and free energy landscapes revealed that the compounds could stabilize the TTBK2 protein. Overall, this study would be valuable for the researchers targeting the development of novel TTBK2 inhibitors. American Chemical Society 2023-03-28 /pmc/articles/PMC10099139/ /pubmed/37065061 http://dx.doi.org/10.1021/acsomega.3c00225 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Ahamad, Shahzaib Hema, Kanipakam Gupta, Dinesh Identification of Novel Tau-Tubulin Kinase 2 Inhibitors Using Computational Approaches |
title | Identification
of Novel Tau-Tubulin Kinase 2 Inhibitors
Using Computational Approaches |
title_full | Identification
of Novel Tau-Tubulin Kinase 2 Inhibitors
Using Computational Approaches |
title_fullStr | Identification
of Novel Tau-Tubulin Kinase 2 Inhibitors
Using Computational Approaches |
title_full_unstemmed | Identification
of Novel Tau-Tubulin Kinase 2 Inhibitors
Using Computational Approaches |
title_short | Identification
of Novel Tau-Tubulin Kinase 2 Inhibitors
Using Computational Approaches |
title_sort | identification
of novel tau-tubulin kinase 2 inhibitors
using computational approaches |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099139/ https://www.ncbi.nlm.nih.gov/pubmed/37065061 http://dx.doi.org/10.1021/acsomega.3c00225 |
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