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...
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Series: | Tuberculosis Research and Treatment |
Online Access: | http://dx.doi.org/10.1155/2013/670836 |
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doaj-9ce2690a56014348ae5e531556571dad2020-11-24T22:38:46ZengHindawi LimitedTuberculosis Research and Treatment2090-150X2090-15182013-01-01201310.1155/2013/670836670836Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosisLuc Calvin Owono Owono0Melalie Keita1Eugene Megnassan2Vladimir Frecer3Stanislav Miertus4Laboratory for Simulations and Biomolecular Physics, Advanced Teachers Training College, University of Yaoundé I, P.O. Box 47, Yaoundé, CameroonInternational Centre for Science and High Technology, UNIDO, Area Science Park, Padriciano 99, 34012 Trieste, ItalyInternational Centre for Science and High Technology, UNIDO, Area Science Park, Padriciano 99, 34012 Trieste, ItalyInternational Centre for Science and High Technology, UNIDO, Area Science Park, Padriciano 99, 34012 Trieste, ItalyInternational Centre for Science and High Technology, UNIDO, Area Science Park, Padriciano 99, 34012 Trieste, ItalyWe 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 (ΔΔGcom) and Ki values explains 94% of the TMPKmt inhibition (pKi=-0.2924ΔΔGcom+3.234;R2=0.94) by variation of the computed ΔΔGcom and 92% for the pharmacophore (PH4) model (pKi=1.0206×pKipred-0.0832, R2=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 Ki 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.http://dx.doi.org/10.1155/2013/670836 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Luc Calvin Owono Owono Melalie Keita Eugene Megnassan Vladimir Frecer Stanislav Miertus |
spellingShingle |
Luc Calvin Owono Owono Melalie Keita Eugene Megnassan Vladimir Frecer Stanislav Miertus Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis Tuberculosis Research and Treatment |
author_facet |
Luc Calvin Owono Owono Melalie Keita Eugene Megnassan Vladimir Frecer Stanislav Miertus |
author_sort |
Luc Calvin Owono Owono |
title |
Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis |
title_short |
Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis |
title_full |
Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis |
title_fullStr |
Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis |
title_full_unstemmed |
Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis |
title_sort |
design of thymidine analogues targeting thymidilate kinase of mycobacterium tuberculosis |
publisher |
Hindawi Limited |
series |
Tuberculosis Research and Treatment |
issn |
2090-150X 2090-1518 |
publishDate |
2013-01-01 |
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 (ΔΔGcom) and Ki values explains 94% of the TMPKmt inhibition (pKi=-0.2924ΔΔGcom+3.234;R2=0.94) by variation of the computed ΔΔGcom and 92% for the pharmacophore (PH4) model (pKi=1.0206×pKipred-0.0832, R2=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 Ki 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. |
url |
http://dx.doi.org/10.1155/2013/670836 |
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