title: 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 ΔΔG(bind-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 (ΔΔG(bind-Expt) of 3.570 and 2.988 kcal/mol, derived from K(d) 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.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA. pnaik2@emory.edu
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Naik
authors.forename: Seneha
authors.initials: S
authors.lastname: Santoshi
authors.forename: Ankit
authors.initials: A
authors.lastname: Rai
authors.forename: Harish C
authors.initials: HC
authors.lastname: Joshi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000996:Antitussive Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003078:Colchicine / Q000737:chemistry / Q000378:metabolism; D006041:Goats; D006801:Humans; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D009665:Noscapine / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000996:Antitussive Agents; D014404:Tubulin; D009665:Noscapine; D003078:Colchicine