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Rational design, synthesis and biological evaluations of amino-noscapine: a high affinity tubulin-binding noscapinoid

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Title Rational design, synthesis and biological evaluations of amino-noscapine: a high affinity tubulin-binding noscapinoid
 
Creator NAIK, PK
CHATTERJI, BP
VANGAPANDU, SN
ANEJA, R
CHANDRA, R
KANTEVERI, S
JOSHI, HC
 
Subject MOLECULAR-ORBITAL METHODS
VALENCE BASIS-SETS
ELECTRON CRYSTALLOGRAPHY
MICROTUBULE DYNAMICS
ACCURATE DOCKING
2ND-ROW ELEMENTS
PERTURB MITOSIS
OVARIAN-CANCER
PROTEIN
CELLS
Noscapine
Amino-noscapine
Free energy of binding
Tubulin binding affinity
Anti-tumor activity
 
Description Noscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding free energies (Delta G (bind)) of noscapinoids computed using linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model were in agreement with the experimental Delta G (bind) with average root mean square error of 0.082 kcal/mol. This LIE-SGB model guided us in designing a novel derivative of noscapine, amino-noscapine [(S)-3-((R)-9-amino-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy isobenzo-furan-1(3H)-one] that has higher tubulin binding activity (predicted Delta G (bind) = -6.438 kcal/mol and experimental Delta G (bind) = -6.628 kcal/mol) than noscapine, but does not significantly change the total extent of the tubulin subunit/polymer ratio. The modes of interaction of amino-noscapine with the binding pocket of tubulin involved three hydrogen bonds and are distinct compared to noscapine which involved only one hydrogen bond. Also the patterns of non-bonded interactions are albeit different between both the lignads. The 'blind docking' approach (docking of ligand with different binding sites of a protein and their evaluations) as well as the reasonable accuracy of calculating Delta G (bind) using LIE-SGB model constitutes the first evidence that this class of compounds binds to tubulin at a site overlapping with colchicine-binding site or close to it. Our results revealed that amino-noscapine has better anti-tumor activity than noscapine.
 
Publisher SPRINGER
 
Date 2012-06-26T05:26:24Z
2012-06-26T05:26:24Z
2011
 
Type Article
 
Identifier JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,25(5)443-454
0920-654X
http://dx.doi.org/10.1007/s10822-011-9430-4
http://dspace.library.iitb.ac.in/jspui/handle/100/13965
 
Language English