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Targeting aurora kinase a (AURKA) in cancer: molecular docking and dynamic simulations of potential AURKA inhibitors

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Abstract

The Aurora family of serine/threonine kinases in mammals are key regulators of mitotic progression and are commonly upregulated in human tumors. Since AURKA’s increased expression has been linked to cancer, AURKA inhibitors could reduce AURKA expression and function as potent therapeutic drugs. The study’s objective was to find and categorize inhibitors with a stronger affinity for AURKA. This study also aimed to identify AURKA’s expression profile and prognostic significance across pan-cancers. We looked into therapeutic compounds that were structurally comparable to MK8745 for their potential to selectively inhibit AURKA. We used drug likeliness analysis, MD simulation studies to evaluate the therapeutic possibility of screened MK8745 analogues. AURKA was found to be strongly upregulated in several cancers and is linked to worse overall and relapse-free survival. The Molecular docking and dynamic analysis revealed two new MK8745 analogues to be potent AURKA inhibitors with higher binding affinities and stabilities than MK8745. Furthermore, MK8745 analogues are potential replacements for MK8745 because they have strong binding affinity, which is consistent with MDS results, and have appropriate ADMET properties. Through basic, clinical, and preclinical research, the identification of novel compounds may open the door for their prospective use in the prevention of cancer.

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Data availability

The breast cancer dataset utilized for the study is freely available at https://portal.gdc.cancer.gov/projects/TCGA-BRCA and survival data can be accessed at https://kmplot.com/analysis/index.php?p=service&cancer=breast

Abbreviations

BLCA:

Bladder urothelial carcinoma

ESCA:

Esophageal carcinoma

BRCA:

Breast invasive carcinoma

LIHC:

Liver hepatocellular carcinoma

HNSC:

Head and neck squamous cell carcinoma

KIRC:

Kidney renal clear cell carcinoma

STAD:

Stomach adenocarcinoma

LUAD:

Lung adenocarcinoma

PADA:

Pancreatic ductal adenocarcinoma

OV:

Ovarian serous cystadenocarcinoma

RCC:

Renal cell carcinoma

PDAC:

Pancreatic ductal adenocarcinoma

UCEC:

Uterine corpus endometrial carcinoma

KIRP:

Kidney renal papillary cell carcinoma

LIHC:

Liver hepatocellular carcinoma

SARC:

Sarcoma

MDS:

Molecular dynamic simulation

Rg:

Radius of gyration

SASA:

Solvent accessible surface area

RFS:

Relapse free survival

OS:

Overall survival

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Acknowledgements

The author would like to thank Department of Family and Community Medicine, Faculty of Medicine, Albaha University, Albaha-65511, KSA for their support.

Funding

The author would like to thank Deanship of Scientific Research et al. AlBaha University for supporting this work under Project Number No. R-2022-XXX.

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  1. Department of Family and Community Medicine, Faculty of Medicine, Albaha University, Albaha, 65511, Kingdom of Saudi Arabia

    Abdullah Almilaibary

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Almilaibary, A. Targeting aurora kinase a (AURKA) in cancer: molecular docking and dynamic simulations of potential AURKA inhibitors. Med Oncol 39, 246 (2022). https://doi.org/10.1007/s12032-022-01852-3

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