Further Insight into the Interactions of the Cytotoxic Macrolides Laulimalide and Peloruside A with Their Common Binding Site

The binding site of the macrolides laulimalide and peloruside A, which is different from that of the clinically useful drugs paclitaxel/taxol and ixabepilone ( tax site ), is known to be between two adjacent β-tubulin units ( ext site ). Here, we report our study of the binding of these molecules to an α1β1/α2β2-tubulin "tetramer" model. AutoDock 4.2.6//AutoDock Vina dockings predicted that the affinities of laulimalide and peloruside A for the tax site are quite similar to those for the ext site . However, molecular dynamics (MD) simulations indicated that only when these two ligands are located at the ext site , there are contacts that help stabilize the system, favoring the β1/β2 interactions. The binding affinity of laulimalide for this site is stronger than that of peloruside A, but this is compensated for by additional β1/β2 contacts that are induced by peloruside A. MD studies also suggested that epothilones at the tax site and either laulimalide or peloruside A at the ext site cause similar stabilizing effects (mainly linking the M-loop of β1 and loop H1-B2 of β2). In a "hexamer" model (3 units of αβ-tubulin), the effects are confirmed. Metadynamics simulations of laulimalide and peloruside A, which are reported for the first time, suggest that peloruside A produces a stronger change in the M-loop, which explains the stabilization of the β1/β2 interaction.