3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods

Vasudevan, Aparna; Jeevan, J.; Ravi, Malini; Desiraju, Gautam R.; Bulusu, Gopalakrishnan

doi:10.1016/j.bmcl.2005.10.086

Cited by 23 publications

(12 citation statements)

References 12 publications

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“…Again the same collection of 47 inhibitors of TMPKmt were selected either as the training or as the test set. One model out of three proved to be more predictive and was claimed informative about the chemical and structural features for TMPKmt inhibition [40].…”

Section: -Computational Proceduresmentioning

confidence: 99%

“…Based on a restricted set of 47 inhibitors of TMPKmt modified on the 5-, 2'-, 3'-and 5'-positions of dTMP (described above), the groups of Gopalakrishnan and Desijaru have developed models either to perform virtual screening [39] or 3D-QSAR analysis [40]. Both approaches take advantage of the solved 3D-structure of TMPKmt with dTMP [11].…”

Section: -Computational Proceduresmentioning

confidence: 99%

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Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

Calenbergh¹,

Pochet²,

Munier‐Lehmann³

2012

CTMC

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Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases and preclude DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. TMPKmt, which is essential to DNA replication, was selected as a promising target for inhibitor design. This review will describe how stepwise modifications of the enzyme's substrate, guided by the feedback of the enzyme assays as well as crystallographic information, proved a valuable approach to produce potent TMPKmt inhibitors, some of which were also capable to inhibit bacterial growth. Perhaps more importantly, some of the reported thymidine analogues also represent valuable tools to better understand the structure and the mechanism of this intriguing enzyme.

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Section: -Computational Proceduresmentioning

confidence: 99%

Section: -Computational Proceduresmentioning

confidence: 99%

Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

Calenbergh¹,

Pochet²,

Munier‐Lehmann³

2012

CTMC

View full text Add to dashboard Cite

show abstract

“…ion present near this position. Thus, nonpolar substituents at GC5 may displace water molecules that otherwise occupy the coordination sites of the metal atom and, thereby, decrease the inhibitory potency [14].…”

Section: Analysis Of the Overall Data Setmentioning

confidence: 99%

“…Recently, a X-ray crystal structure of TMPKmt in complex with dTMP was solved at a resolution of 1.95 Å (PDB entry code 1G3U) [8] allowing the structure-based design of TMPKmt inhibitors. Still, several TMPKmt inhibitors have been synthesized [9][10][11][12], but very few structure-activity relationship studies have been reported [13][14][15]. Overall, TMPKmt represents an attractive potential target for the rational design of new tuberculostatic drugs.…”

Section: Introductionmentioning

confidence: 96%

3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents

Andrade

Pasqualoto

Ferreira

et al. 2010

J Comput Aided Mol Des

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Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r(2) ranging from 0.83 to 0.92 and q(2) from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.

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“…Approximately, one-third of world's population is infected with TB bacillus, Mycobacterium tuberculosis, with more than 8 million people contracting the disease and two million people dying of it each year (Aparna et al, 2006). A peculiar aspect of its pathogenicity comes from the fact that it can remain quiescent and become active decades later.…”

Section: Introductionmentioning

confidence: 99%

Hansch analysis for the prediction of antimycobacterial activity of ofloxacin derivatives

et al. 2010

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The present study was attempted to predict the antimycobacterial activity of ofloxacin derivatives. The QSAR results indicated the importance of electronic properties of molecules viz. energy of the lowest unoccupied molecular orbital (LUMO), total energy (T e ), dipole moment (l) and the topological parameter, third order shape index Kappa (j 3 ) in describing the antimycobacterial activity of ofloxacin derivatives. The validity of developed models has been supported by significant statistical parameters.

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3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods

Cited by 23 publications

References 12 publications

Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents

Hansch analysis for the prediction of antimycobacterial activity of ofloxacin derivatives

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