Title
Molecular modelling and competition binding study of Br-noscapine and colchicine provide insight into noscapinoid–tubulin binding site
Author
Pradeep K. Naik, Seneha Santoshi, Ankit Rai, Harish C. Josh
Year
2011
Journal
Journal of Molecular Graphics and Modelling
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.
Instrument
FP-6500
Keywords
Fluorescence, Ligand binding, Pharmaceutical, Biochemistry