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
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Creator |
NAIK, PK
CHATTERJI, BP VANGAPANDU, SN ANEJA, R CHANDRA, R KANTEVERI, S JOSHI, HC |
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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 |
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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.
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Publisher |
SPRINGER
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Date |
2012-06-26T05:26:24Z
2012-06-26T05:26:24Z 2011 |
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Type |
Article
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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 |
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Language |
English
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