QM and QM/MD simulations of the Vinca alkaloids docked to tubulin.

The Vinca alkaloids are a class of pharmaceutically relevant binary indole-indoline alkaloids based on and including natural extracts of the periwinkle plant, Catharanthus rosea. Two natural products, vinblastine and vincristine, have been in clinical use as important chemotherapy agents for over four decades. Two semi-synthetic Vinca alkaloids, vindesine and vinorelbine, are currently in investigational chemotherapy programs, and a third semi-synthetic, vinflunine, is in advanced clinical trials. In addition to these five compounds studied in the present work, there are hundreds of other natural and semi-synthetic Vinca alkaloids known, although most are not clinically advantageous. The Vinca alkaloids are anti-mitotic agents that affect the cellular protein tubulin and bind to a specific site known as the Vinca domain located on β-tubulin. While the Vinca domain is well established, the specific binding mode of each drug is not. However, there is much insight into the binding mode and this has provided a strong base of information to begin simulations and to make comparisons against. Complicating the issue, however, is the large size of the Vinca alkaloids and their complex molecular structure, including a rotatable single bond joining the indole and indoline portions of each compound. The differential geometric and tubulin-binding properties of the drugs are not fully known. In the present work, the projection of the potential energy surface on the major torsional angle was calculated at the semi-empirical AM1 level, through in vacuo geometry optimizations. QM/MD simulations were performed, with the drugs at the AM1 level, of each Vinca alkaloid free in TIP3P water, and also bound to β-tubulin. A single equilibrium structure, resembling a known crystallographic vinblastine structure, for the free drugs was found. Further, the 1Z2B crystal structure of vinblastine bound to tubulin appears to be a valid starting point for simulations of all five Vinca alkaloids studied here.