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

J Comput Aided Mol Des. 2011 May;25(5):443-54. doi: 10.1007/s10822-011-9430-4. Epub 2011 May 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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