Probing the structure of Leishmania donovani chagasi DHFR-TS: comparative protein modeling and protein–ligand interaction studies
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Probing the structure of Leishmania donovani chagasi
DHFR-TS: comparative protein modeling
and protein–ligand interaction studies
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| Creator |
Maganti, Lakshmi
Manoharan, Prabu Ghoshal, Nanda |
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| Subject |
Structural Biology & Bioinformatics
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| Description |
Dihydrofolate reductase (DHFR) has been used
successfully as a drug target in the area of anti-bacterial,
anti-cancer and anti-malarial therapy. It also acts as a drug
target for Leishmaniasis. Inhibition of DHFR leads to cell
death through lack of thymine (nucleotide metabolism).
Although the crystal structures of Leishmania major and
Trypanosoma cruzi DHFR-thymidylate synthase (TS) have
been resolved, to date there is no three-dimensional (3D)-
structural information on DHFR-TS of Leishmania donovani
chagasi, which causes visceral leishmaniasis. Our aim
in this study was to model the 3D structure of L. donovani
chagasi DHFR-TS, and to investigate the structural requirements
for its inhibition. In this paper we describe a highly
refined homology model of L. donovani chagasi DHFR-TS
based on available crystallographic structures by using the
Homology module of Insight II. Structural refinement and
minimization of the generated L. donovani chagasi DHFRTS
model employed the Discover 3 module of Insight II
and molecular dynamic simulations. The model was further
validated through use of the PROCHECK, Verify_3D,
PROSA, PSQS and ERRAT programs, which confirm that
the model is reliable. Superimposition of the model
structure with the templates L. major A chain, L. major B
chain And T. cruzi A chain showed root mean square
deviations of 0.69 Å, 0.71 Å and 1.11 Å, respectively.
Docking analysis of the L. donovani chagasi DHFR-TS
model with methotrexate enabled us to identify specific
residues, viz. Val156, Val30, Lys95, Lys75 and Arg97,
within the L. donovani chagasi DHFR-TS binding pocket,
that play an important role in ligand or substrate binding. Docking studies clearly indicated that these five residues
are important determinants for binding as they have strong
hydrogen bonding interactions with the ligand.
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| Publisher |
Springer Verlag
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| Date |
2010
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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/76/1/JOURNAL_OF_MOLECULAR_MODELING_16_(9)1539%2D1547;2010[52].pdf
Maganti, Lakshmi and Manoharan, Prabu and Ghoshal, Nanda (2010) Probing the structure of Leishmania donovani chagasi DHFR-TS: comparative protein modeling and protein–ligand interaction studies. Journal of Molecular Modeling, 16. pp. 1539-1547. |
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| Relation |
http://dx.doi.org/10.1007/s00894-010-0649-0
http://www.eprints.iicb.res.in/76/ |
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