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

Content Provider	Springer Nature Link
Author	Andrade, Carolina Horta Pasqualoto, Kerly F. M. Ferreira, Elizabeth I. Hopfinger, Anton J.
Copyright Year	2010
Abstract	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.
Starting Page	157
Ending Page	172
Page Count	16
File Format	PDF
ISSN	0920654X
Journal	Journal of Computer-Aided Molecular Design
Volume Number	24
Issue Number	2
e-ISSN	15734951
Language	English
Publisher	Springer Netherlands
Publisher Date	2010-03-10
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	4D-QSAR 3D-Pharmacophore Thymidine monophosphate kinase TMPK inhibitors Antituberculosis agents Computer Applications in Chemistry Animal Anatomy / Morphology / Histology Physical Chemistry
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Physical and Theoretical Chemistry Computer Science Applications

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