Anti-Tubercular Drug Designing by Structure based Screening of Combinatorial Libraries
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Anti-Tubercular Drug Designing by Structure based Screening
of Combinatorial Libraries
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| Creator |
Ghosh, Payel
Bagchi, Manish C |
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| Subject |
Structural Biology & Bioinformatics
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| Description |
In the current study, the applicability and scope
of descriptor based QSAR models to complement virtual
screening using molecular docking approach have been
applied to identify potential virtual screening hits targeting
DNA gyrase A from Mycobacterium tuberculosis, an
effective and validated anti-mycobacterial target. Initially
QSAR models were developed against M. fortuitum and M.
smegmatis using a series of structurally related fluoroquinolone
derivatives as DNA gyrase inhibitors. Both the
QSAR models yielded significant cross validated Q(2)
values of 0.6715 and 0.6944 and R(2) values of 0.7250 and
0.7420, respectively. The statistically significant models
were validated by a test set of 22 compounds with
predictive R(2) value of 0.7562 and 0.7087 for M. fortuitum
and M. smegmatis respectively. To aid the creation of novel
antituberculosis compounds, combinatorial library was
developed on fluoroquinolone template to derive a data
set of 5280 compounds whose activity values have been
measured by the above models. Highly active compounds
predicted from the models were subjected to molecular
docking study to investigate the mechanism of drug
binding with the DNA gyrase A protein of M. tuberculosis
and the compounds showing similar type of binding
patterns with that of the existing drug molecules, like
sparfloxacin, were finally reported. It is seen that hydrophobic
characteristics of molecular structure together with
few hydrogen bond interactions are playing an essential
role in antimicrobial activity for the fluoroquinolone derivatives. A representative set of seven compounds with
high predicted MIC values were sorted out in the present
study.
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| Publisher |
Springer Verlag
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| Date |
2011
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/116/1/JOURNAL_OF_CELLULAR_PHYSIOLOGY%2C226(1)%2C158%2D164%2C2011[112].pdf
Ghosh, Payel and Bagchi, Manish C (2011) Anti-Tubercular Drug Designing by Structure based Screening of Combinatorial Libraries. Journal of Molecular Modeling, 17. pp. 1607-1620. |
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| Relation |
http://dx.doi.org/10.1007/s00894-010-0861-y
http://www.eprints.iicb.res.in/116/ |
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