G. La Sala, N. Olieric, A. Sharma, F. Viti, F.D.A.B. Perez, L. Huang, J.R. Tonra, G.K. Lloyd, S. Decherchi, J.F. Díaz and M.O. Steinmetz (2019).
Chem, 5, P2969-2986.

αβ-Tubulin is a validated target for anticancer drug discovery, and molecules binding to this protein are used to treat several types of tumors. Here, we report on a combined X-ray crystallography and molecular dynamics approach to study drug binding within the colchicine site of αβ-tubulin, focusing on plinabulin, an agent currently in phase 3 clinical testing for the treatment of cancer and chemotherapy-induced neutropenia. We found that plinabulin is more persistently bound to the colchicine site of βII- compared to βIII-tubulin, allowing for a prediction of isotype-expression-dependent drug sensitivity. Additionally, computational residence time and exit paths from the βII-tubulin were compared between plinabulin and two other compounds, colchicine and combretastatin-A4. The former displayed the highest residence time, followed by plinabulin and then distantly by combretastatin-A4. Our combined experimental and computational protocol could help to investigate anti-tubulin drugs, improving our understanding of their mechanism of action, residence time, and tubulin isotype selectivity.

This work describes an example of using Smoothed or Scaled Molecular Dynamics (Scaled MD) in kinetic calculations.