Abstract
Microtubules are a favorable target for development of anticancer agents. In this study, the anti-proliferative activities of plinabulin and six diketopiperazine derivatives were evaluated against human lung cancer cell line NCI-H460 and human pancreatic cancer cell line BxPC-3. The inhibition activities on these microtubules were assessed by tubulin polymerization and immunofluorescence assays. To gain insight into the interaction mechanism of the derivatives and tubulin, a molecular dynamics simulation was performed. We discovered that the diketopiperazine derivatives could prevent tubulin assembly through conformational changes. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM-PBSA) calculations showed that the trend of the binding free energies of these inhibitors was in agreement with the trend of their biological activities. Introducing hydrophobic groups into the A-ring was favorable for binding. Energy decomposition indicated that van der Waals interaction played an essential role in the binding affinity of tubulin polymerization inhibitors. In addition, the key residues responsible for inhibitor binding were identified. In summary, this study provided valuable information for development of novel tubulin polymerization inhibitors as anticancer agents.
Highlights
Microtubules (MTs) are typically formed by 13 proto laments associating laterally in parallel to form a hollow and polar cylinder
The binding free energy decomposition showed that van der Waals interactions were dominant for the binding affinity
The total binding free energy was decomposed into each residue
Summary
Plinabulin was developed from the natural cyclic diketopiperazine (DKP) derivative ‘‘phenylahistin”, which was isolated from Aspergillus ustus.[14,15] Currently, plinabulin is in phase III clinical trial for treatment of non-small cell lung cancer.[16] For structure–activity relationship study, a series of diketopiperazine (DKP) derivatives were synthesized and their biological activities were evaluated.[17,18] Notably, there was a correlation between the dissociation constants of the inhibitors binding to tubulin (Kd) and the IC50 values against human colon cancer cell lines HT-29.17,18. The structure–activity relationship and interaction mechanisms of the derivatives were explored by molecular docking combined with MD simulation. Both structural analysis and binding free energy calculations provided us valuable information for development of novel tubulin polymerization inhibitors as anticancer agents
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