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 (DGbind) of noscapinoids computed using linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model were in agreement with the experimental DGbind 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 isobenzofuran- 1(3H)-one] that has higher tubulin binding activity (predicted DGbind = -6.438 kcal/mol and experimental DGbind = -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 nonbonded 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 DGbind 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