Exploration of Rate-Limiting Conformational State for 5-[(7-Chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl][1,1¢-biphenyl]-2-ols and Nö-Oxides (Tebuquine Analogues) for Antimalarial Activity Using Molecular Shape Analysis and Molecular Field Analysis Studies
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Exploration of Rate-Limiting Conformational State for
5-[(7-Chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl][1,1¢-biphenyl]-2-ols and Nö-Oxides (Tebuquine Analogues) for Antimalarial Activity Using Molecular Shape
Analysis and Molecular Field Analysis Studies
|
|
| Creator |
Sharma, Pooja
Chhabra, Sandeep Rai, Nitin Ghoshal, Nanda |
|
| Subject |
Structural Biology & Bioinformatics
|
|
| Description |
Tebuquine is a 4-aminoquinoline that shows significantly more potency as an antimalarial than amodiaquine
and chloroquine both in vitro and in vivo. To explore the conformation in the rate-limiting step and to
elucidate pharmacophoric properties of tebuquine-related analogues, molecular shape analysis (MSA) along
with molecular field analysis (MFA) methods were applied on a series of 5-[(7-chloro-4-quinolinyl)amino]-
3-[(alkylamino)methyl][1,1¢-biphenyl]-2-ol analogues and their Nö-oxides possessing antimalarial activity.
The study was performed using 45 compounds in which 37 molecules were taken as a training set for the
derivation of the 3D quantitative structure-activity relationship models and eight molecules were kept as
a test set to evaluate the predictive ability of the derived models. Both methods were analyzed in terms of
their predictive abilities and produced comparable results with good conventional and cross-validated r2
values (0.908 and 0.886, respectively, for the MFA model and 0.846 and 0.812, respectively, for the MSA
model). In external data set prediction, the MSA model scored much better than MFA. Steric, electrostatic,
and hydrogen-bond donor/acceptor fields of molecules were found to be relevant descriptors for structureactivity
relationships. The inclusion of polar solvent-accessible charged surface area and spatial descriptors
in the MSA model generation resulted in a model with significant predictive ability for the test set molecules.
This indicates the importance of the orientation of conformationally favored molecules inside the receptor
site and solvation of the charged surfaces of the molecule by a polar solvent for the activity of the molecule.
The results provided the appropriate tools for predicting the affinity of related compounds using a ligandbased
approach, and for guiding the design and synthesis of novel and more potent antimalarial agents.
|
|
| Date |
2007
|
|
| Type |
Article
PeerReviewed |
|
| Format |
application/pdf
|
|
| Identifier |
http://www.eprints.iicb.res.in/352/1/JOURNAL_OF_CHEMICAL_INFORMATION_AND_MODELING%2C47(3)%2C__1087%2D1096%2C2007[90].pdf
Sharma, Pooja and Chhabra, Sandeep and Rai, Nitin and Ghoshal, Nanda (2007) Exploration of Rate-Limiting Conformational State for 5-[(7-Chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl][1,1¢-biphenyl]-2-ols and Nö-Oxides (Tebuquine Analogues) for Antimalarial Activity Using Molecular Shape Analysis and Molecular Field Analysis Studies. J. Chem. Inf. Model., 47 (3). pp. 1087-1096. |
|
| Relation |
http://dx.doi.org/10.1021/ci600570r
http://www.eprints.iicb.res.in/352/ |
|