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Published on: September 20, 2019
Benserazide Perturbs Kif15-kinesin Binding Protein Interaction with Prolonged Metaphase and Defects in Chromosomal
Jomon Sebastian1, Krishnan Rathinasamy1
1School of Biotechnology, National Institute of Technology Calicut, Calicut-673601, India.
Abstract:
The interaction of Kif15 with kinesin binding protein (KBP) is critical for its microtubule localization, bundling of kinetochore microtubules and proper alignment of chromosomes at the metaphase plate. The Kif15-KBP structure was prepared from the crystal structure of Kif15 and nonhomologous model of KBP through docking. Benserazide was retrieved when we did a screening of the ZINC Drug Database using the pharmacophore model generated from the potential binding site on Kif15 in an effort to identify molecules for repurposing as Kif15 inhibitors. Live cell imaging of HeLa cells revealed that benserazide delayed metaphase to anaphase-onset by 47±10 min compared to control cells. Benserazide treatment perturbed the kinetochore and microtubule interaction and inhibited the proliferation of HeLa cells with an IC50 of 101 μM with a mitotic block of 12 %. It did not bind to tubulin in the in vitro assays suggesting that the observed effects could be due to its perturbation of Kif15-KBP interaction.
Insights
Benserazide inhibits Kif15-KBP interaction, delaying cell division and proliferation in HeLa cells. This drug repurposing offers potential as a Kif15 inhibitor for cancer therapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Kinesin family member 15 (Kif15) interaction with kinesin binding protein (KBP) is crucial for microtubule organization and chromosome alignment.
- Disruptions in these processes are implicated in various diseases, including cancer.
Purpose of the Study:
- To identify potential Kif15 inhibitors through drug repurposing.
- To investigate the effects of identified compounds on cell division and proliferation.
Main Methods:
- Kif15-KBP complex structure modeling via docking.
- Pharmacophore-based virtual screening of the ZINC Drug Database.
- Live cell imaging of HeLa cells treated with benserazide.
- In vitro tubulin binding assays.
Main Results:
- Benserazide was identified as a potential Kif15 inhibitor.
- Benserazide treatment delayed metaphase-to-anaphase transition by 47±10 min in HeLa cells.
- Benserazide inhibited HeLa cell proliferation (IC50 = 101 μM) with a 12% mitotic block and perturbed kinetochore-microtubule interactions, without binding to tubulin.
Conclusions:
- Benserazide perturbs Kif15-KBP interaction, impacting cell division and proliferation.
- Benserazide shows potential as a Kif15 inhibitor for therapeutic applications, warranting further investigation.
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