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3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis
Inhibitory activities of monocyclic nitroimidazoles against Mycobacterium tuberculosis (Mtb) deazaflavin-dependent nitroreductase (DDN) were modeled by using docking, pharmacophore alignment and comparative molecular similarity indices analysis (CoMSIA) methods. A statistically significant model obt...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270125/ https://www.ncbi.nlm.nih.gov/pubmed/24217328 http://dx.doi.org/10.3390/molecules181113870 |
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author | Lee, Sang-Ho Choi, Minsung Kim, Pilho Myung, Pyung Keun |
author_facet | Lee, Sang-Ho Choi, Minsung Kim, Pilho Myung, Pyung Keun |
author_sort | Lee, Sang-Ho |
collection | PubMed |
description | Inhibitory activities of monocyclic nitroimidazoles against Mycobacterium tuberculosis (Mtb) deazaflavin-dependent nitroreductase (DDN) were modeled by using docking, pharmacophore alignment and comparative molecular similarity indices analysis (CoMSIA) methods. A statistically significant model obtained from CoMSIA was established based on a training set using pharmacophore-based molecular alignment. The leave-one out cross-validation correlation coefficients q(2) (CoMSIA) were 0.681. The CoMSIA model had a good correlation ([Image: see text] /CoMSIA = 0.611) between the predicted and experimental activities against excluded test sets. The generated model suggests that electrostatic, hydrophobic and hydrogen bonding interactions all play important roles for interaction between ligands and receptors. The predicted cell wall permeability (logP(app)) for substrates with high inhibitory activity against Mtb were investigated. The distribution coefficient (logD) range was 2.41 < logD < 2.89 for the Mtb cell wall membrane permeability. The larger the polar surface area is, the better the permeability is. A larger radius of gyration (rgry) and a small fraction of rotatable bonds (f(rtob)) of these molecules leads to higher cell wall penetration ability. The information obtained from the in silico tools might be useful in the design of more potent compounds that are active against Mtb. |
format | Online Article Text |
id | pubmed-6270125 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62701252018-12-20 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis Lee, Sang-Ho Choi, Minsung Kim, Pilho Myung, Pyung Keun Molecules Article Inhibitory activities of monocyclic nitroimidazoles against Mycobacterium tuberculosis (Mtb) deazaflavin-dependent nitroreductase (DDN) were modeled by using docking, pharmacophore alignment and comparative molecular similarity indices analysis (CoMSIA) methods. A statistically significant model obtained from CoMSIA was established based on a training set using pharmacophore-based molecular alignment. The leave-one out cross-validation correlation coefficients q(2) (CoMSIA) were 0.681. The CoMSIA model had a good correlation ([Image: see text] /CoMSIA = 0.611) between the predicted and experimental activities against excluded test sets. The generated model suggests that electrostatic, hydrophobic and hydrogen bonding interactions all play important roles for interaction between ligands and receptors. The predicted cell wall permeability (logP(app)) for substrates with high inhibitory activity against Mtb were investigated. The distribution coefficient (logD) range was 2.41 < logD < 2.89 for the Mtb cell wall membrane permeability. The larger the polar surface area is, the better the permeability is. A larger radius of gyration (rgry) and a small fraction of rotatable bonds (f(rtob)) of these molecules leads to higher cell wall penetration ability. The information obtained from the in silico tools might be useful in the design of more potent compounds that are active against Mtb. MDPI 2013-11-08 /pmc/articles/PMC6270125/ /pubmed/24217328 http://dx.doi.org/10.3390/molecules181113870 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Lee, Sang-Ho Choi, Minsung Kim, Pilho Myung, Pyung Keun 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis |
title | 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis |
title_full | 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis |
title_fullStr | 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis |
title_full_unstemmed | 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis |
title_short | 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis |
title_sort | 3d-qsar and cell wall permeability of antitubercular nitroimidazoles against mycobacterium tuberculosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270125/ https://www.ncbi.nlm.nih.gov/pubmed/24217328 http://dx.doi.org/10.3390/molecules181113870 |
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