AccScience Publishing / IMO / Online First / DOI: 10.36922/imo.6547
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ORIGINAL RESEARCH ARTICLE

Computational identification and molecular characterization of novel Aurora-B kinase inhibitors: Pharmacophore modeling, docking, and molecular dynamics simulations

Athavan Alias Anand Selvam1* ,  Sunil Kumar Bandral2 ,  Parasuraman Pavadai2 ,  Kabilan Senthamaraikannan3
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1 Department of Chemistry, Prayoga Institute of Education Research, Bengaluru, Karnataka, India
2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
3 Department of Chemistry, Annamalai University, Annamalai Nagar, Tamil Nadu, India
IMO, 6547 https://doi.org/10.36922/imo.6547
Submitted: 23 November 2024 | Revised: 11 March 2025 | Accepted: 18 March 2025 | Published: 7 April 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Aurora-B, a serine-threonine kinase, plays a critical role in spindle assembly, chromosome alignment, mitotic checkpoint activation, and cytokinesis. The overexpression of Aurora-B leads to abnormal cell division, multinucleation, and centrosome amplification, contributing to cancer. To identify potential Aurora-B inhibitors, a 3D-quantitative structure-activity relationship study was conducted, leading to the selection of a five-feature pharmacophore model (AADRR) with optimal partial least square parameters for virtual screening. Molecular docking was performed to determine the binding interactions of the candidate ligands with the human Aurora-B: inner centromere protein complex (PDB ID: 4AF3), identifying LYS 106, ALA 157, GLU 161, and PHE 219 as key residues crucial for the enzyme inhibition. Based on virtual screening, pharmacokinetic properties, and docking analysis, five lead compounds were selected from the national cancer institute (NCI) database: Compound 1 (NCI ID: 695163), Compound 2 (NCI ID: 327359), Compound 3 (NCI ID: 721045), Compound 4 (NCI ID: 711797), and Compound 5 (NCI ID: 104546). To clarify the interactions between Aurora-B protein and lead compounds, molecular dynamics simulations were carried out. The results demonstrated strong interactions between the lead compounds and critical active-site residues such as ALA 157 and LYS 106. The active site interactions of the protein-ligand complex were further validated through molecular dynamics simulation studies, providing insights into their binding stability and inhibitory potential.

Graphical abstract
Keywords
Aurora-B kinase
Cytokinesis
3D-quantitative structure-activity relationship
Molecular docking
Molecular dynamics simulations
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Al-Rawi DH, Lettera E, Li J, DiBona M, Bakhoum SF. Targeting chromosomal instability in patients with cancer. Nat Rev Clin Oncol. 2024;21:645-659. doi: 10.1038/s41571-024-00923-w

 

  1. Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila Aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998;17:3052-3065. doi: 10.1093/emboj/17.11.3052

 

  1. Mahajan M, Sarkar A, Mondal S. Cell cycle protein BORA is associated with colorectal cancer progression by AURORA-PLK1 cascades: A bioinformatics analysis. J Cell Commun Signal. 2023;17:773-791. doi: 10.1007/s12079-022-00719-6

 

  1. Azeez KRA, Chatterjee S, Yu C, Golub TR, Sobott F, Elkins JM. Structural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP. Nat Commun. 2019;10(1):3166. doi: 10.1038/s41467-019-11085-0

 

  1. Nguyen AL, Schindler K. Specialize and divide (Twice): Functions of three aurora kinase homologs in mammalian oocyte meiotic maturation. Trends Genet. 2017;33(5):349-363. doi: 10.1016/j.tig.2017.03.005

 

  1. Marumoto T, Zhang D, Saya H. Aurora-A-a guardian of poles. Nat Rev Cancer. 2005;5(1):42-50. doi: 10.1038/nrc1526

 

  1. Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol. 2003;4:842-854. doi: 10.1038/nrm1245

 

  1. Dutertre S, Descamps S, Prigent C. On the role of aurora-A in centrosome function. Oncogene. 2002;21(40):6175-6183. doi: 10.1038/sj.onc.1205775

 

  1. Tsai MY, Wiese C, Cao K, et al. A ran signalling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nat Cell Biol. 2003;5(3):242-248. doi: 10.1038/ncb936

 

  1. Murata-Hori M, Tatsuka M, Wang YL. Probing the dynamics and functions of Aurora-B kinase in living cells during mitosis and cytokinesis. Mol Biol Cell. 2002;13(4):1099-1108. doi: 10.1091/mbc.01-09-0467

 

  1. Kimura M, Matsuda Y, Yoshioka T, Sumi N, Okano Y. Identification and characterization of STK12/Aik2: A human gene related to aurora of Drosophila and yeast IPL1. Cytogenet Cell Genet. 1998;82(3-4):147-152. doi: 10.1159/000015089

 

  1. Gassmann R, Carvalho A, Henzing AJ, et al. Borealin: A novel chromosomal passenger required for stability of the bipolar mitotic spindle. J Cell Biol. 2004;166(2):179-191. doi: 10.1083/jcb.200404001

 

  1. Sasai K, Katayama H, Stenoien DL, et al. Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells. Cell Motil Cytoskeleton. 2004;59(4):249-263. doi: 10.1002/cm.20039

 

  1. Tang A, Gao K, Chu L, Zhang R, Yang J, Zheng J. Aurora kinases: Novel therapy targets in cancers. Oncotarget. 2017;8(14):23937-23954. doi: 10.18632/oncotarget.14893

 

  1. Jacobsen A, Bosch LJW, Kemp SRM, et al. Aurora kinase A (AURKA) interaction with Wnt and Ras-MAPK signalling pathways in colorectal cancer. Sci Rep. 2018;8:7522. doi: 10.1038/s41598-018-24982-z

 

  1. Kanagasabai T, Venkatesan T, Natarajan U, et al. Regulation of cell cycle by MDM2 in prostate cancer cells through Aurora Kinase-B and p21WAF1/CIP1 mediated pathways. Cell Signal. 2020;66:109435. doi: 10.1016/j.cellsig.2019.109435

 

  1. Samimi H, Haghpanah V, Irani S, et al. Transcript-level regulation of MALAT1-mediated cell cycle and apoptosis genes using dual MEK/Aurora kinase inhibitor “BI-847325” on anaplastic thyroid carcinoma. DARU J Pharm Sci. 2019;27(1):1-7. doi: 10.1007/s40199-018-0231-3

 

  1. Noor S, Choudhury A, Raza A, et al. Probing baicalin as potential inhibitor of Aurora kinase B: A step towards lung cancer therapy. Int J Biol Macromol. 2024;258:128813. doi: 10.1016/j.ijbiomac.2023.128813

 

  1. Huang D, Huang Y, Huang Z, Weng J, Zhang S, Gu W. Relation of AURKB over-expression to low survival rate in BCRA and reversine-modulated Aurora-B kinase in breast cancer cell lines. Cancer Cell Int. 2019;19:166. doi: 10.1186/s12935-019-0885-z

 

  1. Morahan BJ, Abrie C, Al-Hasani K, et al. Human aurora kinase inhibitor hesperadin reveals epistatic interaction between plasmodium falciparum PfArk1 and PfNek1 kinases. Commun Biol. 2020;3(1):701. doi: 10.1038/s42003-020-01424-z

 

  1. Kollareddy M, Zheleva D, Džubák P, et al. Identification and characterization of drug resistance mechanisms in cancer cells against Aurora kinase inhibitors CYC116 and ZM447439. bioRxiv. 2020. doi: 10.1101/2020.08.26.268128

 

  1. Martens S, Goossens V, Devisscher L, et al. RIPK1-dependent cell death: A novel target of the Aurora kinase inhibitor Tozasertib (VX-680). Cell Death Dis. 2018;9(2):211. doi: 10.1038/s41419-017-0245-7

 

  1. Ajay Kumar TV, Anand SAA, Loganathan C, Saravanan K, Kabilan S, Parthasarathy V. Design, 3D QSAR modeling and docking of TGF-β type I inhibitors to target cancer. Comput Biol Chem. 2018;76:232-244. doi: 10.1016/j.compbiolchem.2018.07.011

 

  1. Anand SAA, Loganathan C, Thomas NS, Saravanan K, Alphonsa AT, Kabilan S. Synthesis, structure prediction, pharmacokinetic properties, molecular docking and antitumor activities of some novel thiazinone derivative. New J Chem. 2015;39(9):7120-7129. doi: 10.1039/C5NJ01369K

 

  1. Schrödinger. Phase, Version 3.4. New York: LLC; 2014.

 

  1. Schrödinger. Maestro, Version 9.3. New York: LLC; 2014.

 

  1. Elkins JM, Santaguida S, Musacchio A, Knapp S. Crystal structure of human aurora-B in complex with incenp and VX-680. J Med Chem. 2012;55(17):7841-7848. doi: 10.1021/jm3008954

 

  1. Schrödinger. Protein Preparation Wizard; Epik, Version 2.3; Impact, Version 5.7. New York: LLC; 2014.

 

  1. Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc. 1996;118(45):11225-11236. doi: 10.1021/ja9621760

 

  1. Schrödinger. Glide, Version 5.8. New York: LLC; 2014.

 

  1. Schrödinger. Desmond Molecular Dynamics System, 2014, D.E. Shaw Research, Version 3.1, Maestro-Desmond Interoperability Tools, Version 3.1. New York: LLC; 2014.

 

  1. Schrödinger. LigPrep, Version 2.5. New York: LLC; 2014.

 

  1. Saravanan K, Elancheran R, Divakar S, et al. Design, synthesis and biological evaluation of 2-(4-phenylthiazol- 2-yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents. Bioorg Med Chem Lett. 2017;27(5):1199-1204. doi: 10.1016/j.bmcl.2017.01.065

 

  1. Tropsha A, Gramatica P, Gombar VK. The importance of being earnest: Validation is the absolute essential for successful application and interpretation of QSPR models. Mol Inform. 2003;22(1):69-77. doi: 10.1002/qsar.200390007

 

  1. Gramatica P. Principles of QSAR models validation: Internal and external. Mol Inform. 2007;26(5):694-701. doi: 10.1002/qsar.200610151

 

  1. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997;23(1-3):3-25. doi: 10.1016/S0169-409X(96)00423-1

 

  1. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3): 3-26. doi: 10.1016/s0169-409x(00)00129-0

 

  1. Schrödinger. QikProp, Version 3.5. New York: LLC; 2014.

 

  1. Friesner RA, Banks JL, Murphy RB, et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739-1749. doi: 10.1021/jm0306430

 

  1. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79:926-935. doi: 10.1063/1.445869

 

  1. Hoover WG. Canonical dynamics: Equilibrium phase-space distributions. Phys Rev A Gen Phys. 1985;31(3):1695-1697. doi: 10.1103/physreva.31.1695

 

  1. Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys. 1994;101:4177-4189. doi: 10.1063/1.467468

 

  1. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG. A smooth particle mesh Ewald method. J Chem Phys. 1995;103:8577-8859. doi: 10.1063/1.470117

 

  1. Athavan SAA, Loganathan C, Saravanan K, Kabilan S. Comparison of molecular docking and molecular dynamics simulations of 1,3-thiazin-4-one with MDM2 protein. Int Lett Chem Phys Astron. 2015;60:161-167. doi: 10.56431/p-m93n64

 

  1. Tropsha A. Best practices for QSAR model development, validation, and exploitation. Mol Inform. 2010;29(6-7): 476-488. doi: 10.1002/minf.201000061

 

  1. Lian S, Du Z, Chen Q, et al. From lab to clinic: The discovery and optimization journey of PI3K inhibitors. Eur J Med Chem. 2024;277:116786. doi: 10.1016/j.ejmech.2024.116786

 

  1. Ashraf S, Ranaghan KE, Woods CJ, Mulholland AJ, Ul-Haq Z. Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach. Sci Rep. 2021;11:18707. doi: 10.1038/s41598-021-97368-3

 

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