期刊
CHEM
卷 5, 期 11, 页码 2969-2986出版社
CELL PRESS
DOI: 10.1016/j.chempr.2019.08.022
关键词
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资金
- BeyondSpring Pharmaceuticals
- Ministerio de Ciencia, Innovacion y Universidades [BFU2016-75319-R]
- Swiss National Science Foundation [31003A_166608]
- Regione Lombardia (Accordo per la Ricerca e l'Innovazione)
alpha beta-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 alpha beta-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 beta II-compared to beta III-tubulin, allowing for a prediction of isotype-expression-dependent drug sensitivity. Additionally, computational residence time and exit paths from the beta II-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.
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