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

Abstract

Noscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding free energies (ΔG (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 ΔG (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 ΔG (bind) = -6.438 kcal/mol and experimental ΔG (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 ΔG (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.

• Authors: Pradeep K Naik, Biswa Prasun Chatterji, Surya N Vangapandu, Ritu Aneja, Ramesh Chandra, Srinivas Kanteveri, Harish C Joshi
• Journal: Journal of computer-aided molecular design (J Comput Aided Mol Des) Vol. 25 Issue 5 Pg. 443-54 (May 2011) ISSN: 1573-4951 [Electronic] Netherlands
• PMID: 21544622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 9-amino-alpha-noscapine
• Antineoplastic Agents
• Antitussive Agents
• Ligands
• Tubulin
• Noscapine
• Colchicine

Topics

• Antineoplastic Agents (chemistry)
• Antitussive Agents
• Binding Sites
• Colchicine (chemistry)
• Drug Design
• Hydrogen Bonding
• Ligands
• Microtubules (chemistry, metabolism)
• Models, Chemical
• Molecular Structure
• Noscapine (analogs & derivatives, chemical synthesis, chemistry)
• Polymerization
• Protein Binding
• Thermodynamics
• Tubulin (chemistry, metabolism)