Tubulin-based Structure-affinity Relationships for Antimitotic Vinca Alkaloids

• DOI: 10.2174/187152012800228841
• Publication Date: 2012-07-15T18:41:52Z
• Authors: Claire Coderch; Antonio Morreale; Federico Gago
• Keywords: 0301 basic medicine; Binding Sites; Vinca alkaloids; Sequence Homology, Amino Acid; Antimitotic drugs; Molecular Sequence Data; Halichondria okadai; Molecular dynamics; Antimitotic Agents; Molecular Dynamics Simulation; Vinblastine; Antineoplastic Agents, Phytogenic; Protein Structure, Tertiary; Structure-Activity Relationship; 03 medical and health sciences; Binding energy analysis; Tubulin; Truncated octahedron; Colchicine-binding; Amino Acid Sequence; Vinca Alkaloids; Computer simulations

The Vinca alkaloids are a group of widely used anticancer drugs, originally extracted from the Madagascar periwinkle, that disrupt microtubule dynamics in mammalian cells by interfering with proper assembly of α,β-tubulin heterodimers. They favor curved tubulin assemblies that destabilize microtubules and induce formation of spiral aggregates. Their binding energy profiles have been characterized by means of sedimentation velocity assays and the binding site of vinblastine at the interface between two tubulin dimers (α1β1 � α2β2) has been ascertained by X-ray crystallographic studies on a complex of tubulin with the stathmin-like domain of protein RB3, albeit at relatively low resolution. Here we use molecular modeling and simulation techniques to build, refine and perform a comparative analysis of the three-dimensional complexes of vinblastine, vincristine, vinorelbine and vinflunine with a β1α2-tubulin interface in explicit water to rationalize the binding affinity differences in structural and energetic terms. Our results shed some more light into the binding determinants and the structure-activity relationships of these clinically useful agents.