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Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis
We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natu...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619541/ https://www.ncbi.nlm.nih.gov/pubmed/23634301 http://dx.doi.org/10.1155/2013/670836 |
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author | Owono Owono, Luc Calvin Keita, Melalie Megnassan, Eugene Frecer, Vladimir Miertus, Stanislav |
author_facet | Owono Owono, Luc Calvin Keita, Melalie Megnassan, Eugene Frecer, Vladimir Miertus, Stanislav |
author_sort | Owono Owono, Luc Calvin |
collection | PubMed |
description | We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔG (com)) and K (i) values explains 94% of the TMPKmt inhibition (pK (i) = −0.2924ΔΔG (com) + 3.234; R (2) = 0.94) by variation of the computed ΔΔG (com) and 92% for the pharmacophore (PH4) model (pK (i) = 1.0206 × pK (i) (pred) − 0.0832, R (2) = 0.92). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predicted K (i) of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents. |
format | Online Article Text |
id | pubmed-3619541 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-36195412013-04-30 Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis Owono Owono, Luc Calvin Keita, Melalie Megnassan, Eugene Frecer, Vladimir Miertus, Stanislav Tuberc Res Treat Research Article We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔG (com)) and K (i) values explains 94% of the TMPKmt inhibition (pK (i) = −0.2924ΔΔG (com) + 3.234; R (2) = 0.94) by variation of the computed ΔΔG (com) and 92% for the pharmacophore (PH4) model (pK (i) = 1.0206 × pK (i) (pred) − 0.0832, R (2) = 0.92). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predicted K (i) of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents. Hindawi Publishing Corporation 2013 2013-03-24 /pmc/articles/PMC3619541/ /pubmed/23634301 http://dx.doi.org/10.1155/2013/670836 Text en Copyright © 2013 Luc Calvin Owono Owono et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Owono Owono, Luc Calvin Keita, Melalie Megnassan, Eugene Frecer, Vladimir Miertus, Stanislav Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis |
title | Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis
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title_full | Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis
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title_fullStr | Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis
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title_full_unstemmed | Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis
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title_short | Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis
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title_sort | design of thymidine analogues targeting thymidilate kinase of mycobacterium tuberculosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619541/ https://www.ncbi.nlm.nih.gov/pubmed/23634301 http://dx.doi.org/10.1155/2013/670836 |
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