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An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies
BACKGROUND: Tubulin protein being the fundamental unit of microtubules is actively involved in cell division thus making them a potential anti-cancer drug target. In spite of many reported drugs against tubulin, few of them have started developing resistance in human β-tubulin due to amino acid subs...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Avicenna Research Institute
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009099/ https://www.ncbi.nlm.nih.gov/pubmed/24834310 |
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author | Chellasamy, Selvaakumar Mohammed, Sudheer M. M. |
author_facet | Chellasamy, Selvaakumar Mohammed, Sudheer M. M. |
author_sort | Chellasamy, Selvaakumar |
collection | PubMed |
description | BACKGROUND: Tubulin protein being the fundamental unit of microtubules is actively involved in cell division thus making them a potential anti-cancer drug target. In spite of many reported drugs against tubulin, few of them have started developing resistance in human β-tubulin due to amino acid substitutions. METHODS: In this study we generated three mutants (F270V, A364T and Q292E) using Modeller9v10 which were targeted with compounds from higher and lower plants along with marine isolates using iGEMDOCK2.0 to identify their residual interactions. RESULTS: The mutant F270V does not bring in any increase in the binding affinity in comparison with the taxol-wild type due to their conservative substitutions. However, it increases the volume of the active site. A364T mutant brings a better binding among few of the marine and higher plants isolates due to the substitution of the non-reactive methyl group with the polar residue. But this leads to reduced active site volume. Finally the mutant Q292E from epothilone binding site brings a remarkable change in drug binding in the mutants in comparison with the wild type due to the substitution of uncharged residue with the charged one. But as such there was no change in the volume of the active site observed in them. CONCLUSION: Lower plants extracts were reported to exhibit better interactions with the taxol and epothilone binding sites. Whereas marine and higher plants isolates shows significant interactions only in the wild type instead of the mutants. In addition to this, the residual substitutions were also found to alter the conformations of the active sites in mutants |
format | Online Article Text |
id | pubmed-4009099 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Avicenna Research Institute |
record_format | MEDLINE/PubMed |
spelling | pubmed-40090992014-05-15 An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies Chellasamy, Selvaakumar Mohammed, Sudheer M. M. Avicenna J Med Biotechnol Original Article BACKGROUND: Tubulin protein being the fundamental unit of microtubules is actively involved in cell division thus making them a potential anti-cancer drug target. In spite of many reported drugs against tubulin, few of them have started developing resistance in human β-tubulin due to amino acid substitutions. METHODS: In this study we generated three mutants (F270V, A364T and Q292E) using Modeller9v10 which were targeted with compounds from higher and lower plants along with marine isolates using iGEMDOCK2.0 to identify their residual interactions. RESULTS: The mutant F270V does not bring in any increase in the binding affinity in comparison with the taxol-wild type due to their conservative substitutions. However, it increases the volume of the active site. A364T mutant brings a better binding among few of the marine and higher plants isolates due to the substitution of the non-reactive methyl group with the polar residue. But this leads to reduced active site volume. Finally the mutant Q292E from epothilone binding site brings a remarkable change in drug binding in the mutants in comparison with the wild type due to the substitution of uncharged residue with the charged one. But as such there was no change in the volume of the active site observed in them. CONCLUSION: Lower plants extracts were reported to exhibit better interactions with the taxol and epothilone binding sites. Whereas marine and higher plants isolates shows significant interactions only in the wild type instead of the mutants. In addition to this, the residual substitutions were also found to alter the conformations of the active sites in mutants Avicenna Research Institute 2014 /pmc/articles/PMC4009099/ /pubmed/24834310 Text en Copyright © 2014 Avicenna Research Institute http://creativecommons.org/licenses/by-nc/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly. |
spellingShingle | Original Article Chellasamy, Selvaakumar Mohammed, Sudheer M. M. An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies |
title | An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies |
title_full | An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies |
title_fullStr | An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies |
title_full_unstemmed | An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies |
title_short | An In silico Based Comparison of Drug Interactions in Wild and Mutant Human β-tubulin through Docking Studies |
title_sort | in silico based comparison of drug interactions in wild and mutant human β-tubulin through docking studies |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009099/ https://www.ncbi.nlm.nih.gov/pubmed/24834310 |
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