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

J Mol Graph Model. 2011 Jun;29(7):947-55. doi: 10.1016/j.jmgm.2011.03.004. Epub 2011 Apr 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use
  • Antitussive Agents / chemistry
  • Antitussive Agents / metabolism
  • Binding Sites
  • Colchicine* / chemistry
  • Colchicine* / metabolism
  • Goats
  • Humans
  • Models, Chemical*
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Neoplasms / drug therapy
  • Noscapine* / chemistry
  • Noscapine* / metabolism
  • Protein Conformation
  • Tubulin* / chemistry
  • Tubulin* / metabolism

Substances

  • Antineoplastic Agents
  • Antitussive Agents
  • Tubulin
  • Noscapine
  • Colchicine