Download PDF
Drug Res (Stuttg) 2023; 73(01): 30-39
DOI: 10.1055/a-1877-4693
Original Article

Identification and Screening of Novel Anti-Cancer Compounds for Aurora Kinase-A from Chemical Database

Ipsa A. Singh
1   Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
,
Kiran Bharat Lokhande
1   Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, India.
,
K. Venkateswara Swamy
2   Drug Discovery Group, MIT School of Bioengineering Sciences & Research, MIT Art, Design and Technology University, Pune, India.
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Aurora kinase is a group of enzymes that belongs to a serine-threonine family and plays a critical role in cellular division. Aurora Kinase A is overexpressed and distributed beyond the nucleus and is involved in tumorigenesis. Flavones are a class of flavonoids that are present in plants that show anticancer activity. Similar compounds of 2’Fluoroflavones are retrieved from the PubChem database. Then drug-like filters viz. REOS and PAINS were applied to remove toxic compounds using Canvas software, resulting in 3882 compounds being subjected to Glide docking with Aurora kinase A. The lead compounds were selected on the merit of hydrogen bonding, salt bridge, as well as pi-pi interactions, 4-(6-Fluoro-4-oxychromen-2yl) benzoic acid, has been found one of the best molecules from docking studies. The binding mode of the lead compound with AURKA reveals that the amino acid residues viz, Lys162, Ala213, and His280 are more important for binding with the binding affinity of -11.760 kcal/mol. The molecular dynamics simulations of 100 ns were done, which shows the mean RMSD value of 1.77 Å for all 3 complexes of the protein and Fluoroflavone and its analogs. This shows that Fluoroflavone and its 2 best analogs are tightly attached to the active sites and thus have conformational stability. Our finding suggests that 4-(6-fluoro-4-oxochromen-2-yl)benzoic acid and 4-(4-Oxochromen-2-yl)benzoate can be further used in vitro and in vivo experiments and can probably serve as a novel drug for cancer treatment.

Key words

Aurora kinase A - Fluoroflavones - chemoinformatics - Glide docking - MD simulation - Enrichment calculations


Publication History

Received: 28 May 2022

Accepted: 13 June 2022

Article published online:
22 September 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Ma HT, Poon R. Aurora kinases and DNA damage response. Mutation research 2020; 821: 111716
    CrossrefPubMedSearch in Google Scholar
  • 2 Tang A, Gao K, Chu L. et al. Aurora kinases: novel therapy targets in cancers. Oncotarget 2017; 8: 23937-23954
    CrossrefPubMedSearch in Google Scholar
  • 3 Carvalhal S, Ribeiro SA, Arocena M. et al. The nucleoporin ALADIN regulates Aurora A localization to ensure robust mitotic spindle formation. Molecular biology of the cell 26 2015; 3424-3438
    CrossrefPubMedSearch in Google Scholar
  • 4 Kollareddy M, Dzubak P, Zheleva D. et al. Aurora kinases: structure, functions and their association with cancer. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 152 2008; 27-33
    CrossrefPubMedSearch in Google Scholar
  • 5 Kamran M, Long ZJ, Xu D. et al. Aurora kinase A regulates Survivin stability through targeting FBXL7 in gastric cancer drug resistance and prognosis. Oncogenesis 2017; 6: e298
    CrossrefPubMedSearch in Google Scholar
  • 6 Takahashi Y, Sheridan P, Niida A. et al. The AURKA/TPX2 axis drives colon tumorigenesis cooperatively with MYC. Annals of oncology: official journal of the European Society for Medical Oncology 2015; 26: 935-942
    CrossrefPubMedSearch in Google Scholar
  • 7 Nguyen AL, Drutovic D, Vazquez BN. et al. Genetic Interactions between the Aurora Kinases Reveal New Requirements for AURKB and AURKC during Oocyte Meiosis. Current biology : CB 2018; 28: 3458-3468.e5
    CrossrefPubMedSearch in Google Scholar
  • 8 Malumbres M, Pérez de Castro I. Aurora kinase A inhibitors: promising agents in antitumoral therapy. Expert opinion on therapeutic targets 2014; 18: 1377-1393
    CrossrefPubMedSearch in Google Scholar
  • 9 D’Assoro AB, Haddad T, Galanis E. Aurora-A Kinase as a Promising Therapeutic Target in Cancer. Front Oncol 2016; 5: 295 PMID: 26779440; PMCID: PMC4701905 .
    CrossrefPubMedSearch in Google Scholar
  • 10 Matthews N, Visintin C, Hartzoulakis B. et al. Aurora A and B kinases as targets for cancer: will they be selective for tumors. Expert review of anticancer therapy 2006; 6: 109-120
    CrossrefPubMedSearch in Google Scholar
  • 11 Shin SY, Lee Y, Kim BS. et al. Inhibitory Effect of Synthetic Flavone Derivatives on Pan-Aurora Kinases: Induction of G2/M Cell-Cycle Arrest and Apoptosis in HCT116 Human Colon Cancer Cells. International journal of molecular sciences 2018; 19: 4086
    CrossrefPubMedSearch in Google Scholar
  • 12 Xie Y, Zhu S, Zhong M. et al. Inhibition of Aurora Kinase A Induces Necroptosis in Pancreatic Carcinoma. Gastroenterology 2017; 153: 1429-1443.e5
    CrossrefPubMedSearch in Google Scholar
  • 13 Yan M, Wang C, He B. et al. Aurora-A Kinase: A Potent Oncogene and Target for Cancer Therapy. Medicinal research reviews 2016; 36: 1036-1079
    CrossrefPubMedSearch in Google Scholar
  • 14 Lee YH, Park J, Ahn S. et al. Design, synthesis, and biological evaluation of polyphenols with 4,6-diphenylpyrimidin-2-amine derivatives for inhibition of Aurora kinase A. Daru: journal of Faculty of Pharmacy, Tehran University of Medical Sciences 2019; 27: 265-281
    CrossrefPubMedSearch in Google Scholar
  • 15 Long L, Wang YH, Zhuo JX. et al. Structure-based drug design: Synthesis and biological evaluation of quinazolin-4-amine derivatives as selective Aurora A kinase inhibitors. European journal of medicinal chemistry 2018; 157: 1361-1375
    CrossrefPubMedSearch in Google Scholar
  • 16 Katayama H, Sen S. Aurora kinase inhibitors as anticancer molecules. Biochimica et biophysica acta 2010; 1799 (10-12) 829-839
    CrossrefPubMedSearch in Google Scholar
  • 17 Jung Y, Shin SY, Yong Y. et al. Plant-derived flavones as inhibitors of aurora B kinase and their quantitative structure-activity relationships. Chemical biology & drug design 2015; 85: 574-585
    CrossrefPubMedSearch in Google Scholar
  • 18 Libertini S, Abagnale A, Passaro C. et al. Aurora A and B kinases--targets of novel anticancer drugs. Recent patents on anti-cancer drug discovery 2010; 5: 219-241
    CrossrefPubMedSearch in Google Scholar
  • 19 Ma HT, Poon R. Aurora kinases and DNA damage response. Mutation research 2020; 821: 111716
    CrossrefPubMedSearch in Google Scholar
  • 20 van Gijn SE, Wierenga E, van den Tempel N. et al. TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells. Oncogene 2019; 38: 852-867
    CrossrefPubMedSearch in Google Scholar
  • 21 Lokhande KB, Doiphode S, Vyas R. et al. Molecular docking and simulation studies on SARS-CoV-2 Mproreveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19. Journal of biomolecular structure & dynamics 2020; 1-12 Advance online publication
    CrossrefPubMedSearch in Google Scholar
  • 22 Mysinger MM, Carchia M, Irwin JJ. et al. Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. Journal of medicinal chemistry 2012; 55: 6582-6594
    CrossrefPubMedSearch in Google Scholar
  • 23 Chaput L, Martinez-Sanz J, Saettel N. et al. Benchmark of four popular virtual screening programs: construction of the active/decoy dataset remains a major determinant of measured performance. Journal of cheminformatics 2016; 8: 56
    CrossrefPubMedSearch in Google Scholar
  • 24 Lokhande K. B., Apte G. R., Shrivastava A., et al., K Venkateswara Swamy & Gupta R. K. (2020). Sensing the interactions between carbohydrate-binding agents and N-linked glycans of SARS-CoV-2 spike glycoprotein using molecular docking and simulation studies. Journal of biomolecular structure & dynamics, 1–19. Advance online publication. https://doi.org/10.1080/07391102.2020.1851303
    PubMed
  • 25 Mansuri A, Lokhande K, Kore S. et al. Antioxidant, anti-quorum sensing, biofilm inhibitory activities and chemical composition of Patchouli essential oil: in vitro and in silico approach. Journal of biomolecular structure & dynamics 2020; 1-12 Advance online publication
    CrossrefPubMedSearch in Google Scholar