Identification of a novel Aurora B inhibitor using the AI-driven drug screening and docking-based traditional
Jiayuan Ye1, Nan Chen1, Yixiang Zhu2
1Department of Hepatology, Shangyu People's Hospital of Shaoxing, Shaoxing University, Shaoxing, Zhejiang Province, 312399, China.
Abstract:
Aurora B, a subtype of Aurora kinases that functions as a serine/threonine kinase, playing a vital role in the process of mitosis, is often overexpressed in certain tumor cells leading to tumorigenesis and progression. Therefore, the development of small molecule inhibitors targeting Aurora B holds promise for providing new options for some cancer patients. In this study, we efficiently screened 4 compounds from MCE compound database using a combination of machine learning-based screening and structure-based screening. The results showed that 2 compounds exhibited strong Aurora B inhibitory activity in a homogeneous time-resolved fluorescence (HTRF) assay, indicating a high hit rate for this screening method. Among them, compound 4 demonstrated optimal inhibitory activity against Aurora B, with an IC50 value of 15.54 nM, comparable to Aurora B inhibitors that have entered clinical trials. In vitro experiments indicated that compound 4 effectively inhibited Huh-7 and Huh-6 cells, with IC50 values of 0.9 μM and 1.8 μM, respectively. Molecular dynamics simulation results revealed that the compound binds to the ATP binding pocket of Aurora B, forming hydrogen bond interactions with Glu171 and Glu220, salt bridges with Asp234 and Glu177, and a pi-cation interaction with Arg97. In summary, by integrating multi-modal screening approaches, we successfully identified a potent Aurora B inhibitor with in vitro antitumor activity, providing lead compounds for subsequent drug development.
Insights
Researchers identified a potent small molecule inhibitor targeting Aurora B, a kinase overexpressed in tumors. This compound shows promising in vitro antitumor activity, offering potential new cancer treatment options.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Aurora B kinase is a serine/threonine kinase crucial for mitosis.
- Overexpression of Aurora B is linked to tumorigenesis and cancer progression.
- Targeting Aurora B with small molecule inhibitors presents a therapeutic strategy for cancer.
Purpose of the Study:
- To identify novel small molecule inhibitors of Aurora B kinase.
- To evaluate the in vitro antitumor activity of identified compounds.
- To provide lead compounds for further cancer drug development.
Main Methods:
- Utilized a combination of machine learning-based and structure-based screening.
- Screened compounds from the MCE compound database.
- Assessed Aurora B inhibitory activity using homogeneous time-resolved fluorescence (HTRF) assays and in vitro cell-based assays.
- Performed molecular dynamics simulations to elucidate binding interactions.
Main Results:
- Successfully screened and identified two potent Aurora B inhibitors.
- Compound 4 exhibited optimal inhibitory activity (IC50 = 15.54 nM) against Aurora B.
- Compound 4 demonstrated significant inhibition of Huh-7 and Huh-6 cancer cells (IC50 values of 0.9 μM and 1.8 μM, respectively).
- Molecular dynamics simulations revealed key binding interactions within the Aurora B ATP pocket.
Conclusions:
- Integrated multi-modal screening approaches effectively identified a potent Aurora B inhibitor.
- Compound 4 possesses significant in vitro antitumor activity.
- The identified compound serves as a promising lead for developing new cancer therapeutics.
