Molecular modelling and competition binding study of Br-noscapine and colchicine provide insight into noscapinoid–tubulin binding site

Abstract

We have previously discovered the tubulin-binding anti-cancer properties of noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or near the well studied colchicine binding site of tubulin: 1) In silico molecular docking studies of Br-noscapine and noscapine yield highest docking score with the well characterised colchicine-binding site from the co-crystal structure; 2) the molecular mechanics-generalized Born/surface area (MM-GB/SA) scoring results ΔΔGbind-cald for both noscapine and Br-noscapine (3.915 and 3.025 kcal/mol) are in reasonably good agreement with our experimentally determined binding affinity (ΔΔGbind-expt of 3.570 and 2.988 kcal/mol, derived from Kd values); and 3) Br-noscapine competes with colchicine binding to tubulin. The simplest interpretation of these collective data is that Br-noscapine binds tubulin at a site overlapping with, or very close to colchicine-binding site of tubulin. Although we cannot rule out a formal possibility that Br-noscapine might bind to a site distinct and distant from the colchicine-binding site that might negatively influence the colchicine binding to tubulin.

Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell therapy

“…Thus, minimization and then optimization of ligands using OPLS_2005 force field were performed to get one final 3D representative model of all ligands ready to dock. (Naik et al, 2011). For the preparation of protein molecules the crystal structures of protein were imported to the protein preparation wizard application of maestro 9.6 (Naik et al, 2011).…”

“…(Naik et al, 2011). For the preparation of protein molecules the crystal structures of protein were imported to the protein preparation wizard application of maestro 9.6 (Naik et al, 2011). The various step involved in protein preparation steps include preprocess, review, modiefy and refinement.…”

“…Glide docking was performed using flexible extra precession mode provided by Maestro glide (Naik et al, 2011). Docking results were obtained in the form of Glide score which were finally re-scored in the form of binding energy using prime MM-GBSA module provided with Maestro 9.6 (Lyne et al, 2006).…”

In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin)

“…Alternatively, only one piece of experimental evidence (competition interaction of Br-noscapine with colchicine binding) is so far reported that revealed a binding site of noscapinoid at or near the colchicine binding site of tubulin [21]. We reported that Br-noscapine produced a competition of 66% with colchicine at a concentration of 100 lM.…”

“…Computational docking and competition studies of its derivative, 9-bromo-noscapine, point to binding with tubulin at a site overlapping with colchicine binding site [21]. The binding site is located at the interface between a-and b-tubulin and is large in volume (1,109.95 Å 3 ).…”