Description:
<jats:p>Noscapine, the benzylisoquinoline alkaloid, 5‐(4,5‐Dimethoxy‐3‐oxo‐1,3‐dihydro‐isobenzofuran‐1‐yl)‐4‐methoxy‐6‐methyl‐5,6,7,8‐tetrahydro‐[1,3]dioxolo[4,5‐g]isoquinolin‐6‐ium, has been extensively used as a cough‐suppressing medication with low toxicity. It has been recently shown to also have anti‐cancer activity in mice and humans. In this work, using <jats:italic>in silico</jats:italic> analyses, the most probable binding site for noscapine is identified to be at the intradimer region of the α and β subunits of the tubulin heterodimer. By utilization of small molecule docking techniques, and an analysis of the thermodynamically favorable binding modes of noscapine in its binding site, the key residues of tubulin monomers interacting with noscapine are determined. Upon noscapine binding, the conformational change in the tubulin heterodimer along with a potential long‐range allosteric effect on both the N and E sites is studied by means of molecular dynamics simulations. Noscapine is found to function as a tubulin‐stabilizing agent that interacts strongest with the lateral and longitudinal segments of the tubulin dimer, impacting the interaction between monomers in neighboring protofilaments. We infer that this may act as a depolymerization inhibitor of microtubules. As a result of this study, we have designed novel analogues of noscapine with the ultimate goal of finding agents with increased anti‐tumor activity and lower inhibitory concentrations than that of noscapine.</jats:p>