Computational Exploration of Potential Polo-Like Kinase 1 Inhibitors as New Chemotherapeutic Agents

Main Article Content

Mubarak A. Alamri
Ahmed D. Alafnan


Background and Objective: Polo like kinase-1 (PLK-1) enzyme belongs to serine/threonine protein kinase family that is regarded as a principle mitotic controller of G2-M phase transition. The antimitotic therapies are a cornerstone for the treatment of metastatic as well as benign cancer. Therefore, PLK-1 has recently gained much interest in the field of targeting it by novel and effective inhibitors.

Materials and Methods: The present study described the used of pharmacophore modelling based on the potent and selective clinical agent, Volasertib and followed by hybrid selection of a kinase inhibitors databank of 4800 diverse compounds by pharmacophore- and docking-based virtual screening.

Results: The retrieved hits were filtered on the bases of their pharmacophore-fit scores, docking binding affinity scores, ADME-T profiles as well as ligand quality assessments. Among the five hit compounds that fulfil the criterion, three compounds, Z1991791422, Z56115729 and Z1991791176 were selected for binding dynamic analyses by molecular dynamic simulation. The Z1991791422 and Z56115729 compounds illustrated stable binding behaviours at the proposed binding site. Conclusion: Thus, these compounds might emerge as potent inhibitors of PLK1 and could be applied as seeds for designing better PLK1 inhibitors in near future.

Autodock Vina, ligandscout, polo like kinase-1, pharmacophore, virtual screening, molecular simulation.

Article Details

How to Cite
Alamri, M. A., & Alafnan, A. D. (2020). Computational Exploration of Potential Polo-Like Kinase 1 Inhibitors as New Chemotherapeutic Agents. Journal of Pharmaceutical Research International, 32(29), 18-30.
Original Research Article


Ma X, Wang L, Huang D, Li Y, Yang D, Li T, Li F, Sun L, Wei H, He K, Yu F, Zhao D, Hu L, Xing S, Liu Z, Li K, Guo J, Yang Z, Pan X, Li A, Shi Y, Wang J, Gao P, Zhang H. Polo-like kinase 1 coordinates biosynthesis during cell cycle progression by directly activating pentose phosphate pathway. Nat. Commun. 2017;8(1):1506.

Shakil S, Baig MH, Tabrez S, Rizvi SMD, Zaidi SK, Ashraf GM, Ansari SA, Khan AAP, Al-Qahtani MH, Abuzenadah AM, Chaudhary AG. Molecular and enzoinformatics perspectives of targeting polo-like kinase 1 in cancer therapy. Sem. Cancer. Biol. 2019;56:47-55.

Weerdt BCVD, Medema RH. Polo-like kinases: A team in control of the division. Cell Cycle. 2006;5(8):853-64.

Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica JG, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 2017;35(32):3638-3646.

Sumara I, Vorlaufer E, Stukenberg PT, Kelm O, Redemann N, Nigg EA, Peters JM. The dissociation of cohesin from chromosomes in prophase is regulated by Polo-like kinase. Molecul. cell. 2002;9(3): 515-525.

Roshak AK, Capper EA, Imburgia C, Fornwald J, Scott G, Marshall LA. The human polo-like kinase, PLK, regulates cdc2/cyclin B through phosphorylation and activation of the cdc25C phosphatase. Cell. Signalling. 2000;12(6):405-11.

Kotani S, Tugendreich S, Fujii M, Jorgensen PM, Watanabe N, Hoog C, Hieter P, Todokoro K. PKA and MPF-activated polo-like kinase regulate anaphase-promoting complex activity and mitosis progression. Mol. Cell. 1998;1(3): 371-80.

Xu J, Shen C, Wang T, Quan J. Structural basis for the inhibition of Polo-like kinase 1. Nat. Struct. Mol. Biol. 2013;20(9):1047-53.

Weichert W, Schmidt M, Jacob J, Gekeler V, Langrehr J, Neuhaus P, Bahra M, Denkert C, Dietel M, Kristiansen G. Overexpression of polo-like kinase 1 is a common and early event in pancreatic cancer. Pancreatol. 2005;5(2):259-65.

Weichert W, Kristiansen G, Winzer KJ, Schmidt M, Gekeler V, Noske A, Müller BM, Niesporek S, Dietel M, Denkert C. Pololike kinase isoforms in breast cancer: Expression patterns and prognostic implications. Virchows. Arch. 2005;446: 442-50.

Abdelfatah S, Berg A, Böckers M, Efferth T. A selective inhibitor of the Polo-box domain of Polo-like kinase 1 identified by virtual screening. J. Adv. Res. 2019;16: 145-156.

Wolf G, Elez R, Doermer A, Holtrich U, Ackermann H, Stutte HJ, Altmannsberger HM, RuÈbsamen-Waigmann H, Strebhardt K. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene. 1997;14(5):543-49.

Seth S, Matsui Y, Fosnaugh K, Liu Y, Vaish N, Adami R, Harvie P, Johns R, Severson G, Brown T, Takagi A. RNAi-based therapeutics targeting survivin and plk1 for treatment of bladder cancer. Mol. Ther. 2011;19(5):928-35.

Hu K, Law JH, Fotovati A, Dunn SE. Small interfering RNA library screen identified polo-like kinase-1 (PLK1) as a potential therapeutic target for breast cancer that uniquely eliminates tumor-initiating cells. Breast Cancer Res. 2012;14(1):R22.

Rizvi SMD, Shakil S, Zeeshan M, Khan MS, Shaikh S, Biswas D, Ahmad A, Kamal MA. An enzoinformatics study targeting polo-like kinases-1 enzyme: Comparative assessment of anticancer potential of compounds isolated from leaves of Ageratum houstonianum. Pharmacog. Mag. 2014;10:S14-21.

Rizvi SMD, Alshammari AAA, Almawkaa WA, Ahmed ABF, Katamesh A, Alafnan A, Almutairi TJ, Alshammari RF. An oncoinformatics study to predict the inhibitory potential of recent FDA-approved anti-cancer drugs against human Polo-like kinase 1 enzyme: A step towards dual-target cancer medication. 3 Biotech. 2019;9(3):70.

Strebhardt K, Becker S, Matthess Y. Thoughts on the current assessment of Polo-like kinase inhibitor drug discovery. Expert. Opin. Drug. Dis. 2015;10(1):1-8.

Raab M, Pachl F, Krämer A, Kurunci-Csacsko E, Dötsch C, Knecht R, Becker S, Kuster B, Strebhardt K. Quantitative chemical proteomics reveals a Plk1 inhibitor-compromised cell death pathway in human cells. Cell. Res. 2014;24(9): 1141-45.

Alamri MA, Alamri MA. Pharmacophore and docking-based sequential virtual screening for the identification of novel Sigma 1 receptor ligands. Bioinformation. 2019;15(8):586-595.

Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, Haslinger C, Garin-Chesa P, Adolf GR. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin. Cancer Res. 2009;15(9):3094-102.

Wolber G, Langer T. LigandScout: 3-D Pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Info. Model. 2005;45(1):160-69.

Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017;7:42717.

Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic. Acids. Res. 2018;46(W1):W257-W263.

Shakil S, Abuzinadah MF. Putative anti-cancer drug candidate targeting the 'PLK-1-Polo-Box Domain' by high throughput virtual screening: A computational drug design study. Crit. Rev. Eukaryot. Gene. Expr. 2019;29(3):251-61.

Onawole AT, Kolapo TU, Sulaiman KO, Adegoke RO. Structure based virtual screening of the Ebola virus trimeric glycoprotein using consensus scoring. Comput. Biol. Chem. 2018;72:170-80.

Edwards MP, Price DA. Role of physicochemical properties and ligand lipophilicity efficiency in addressing drug safety risks. Annu. Rep. Med. Chem. 2010;45:380-391.

Murray CW, Erlanson DA, Hopkins AL, Keserü GM, Leeson PD, Rees DC, Reynolds CH, Richmond NJ. Validity of ligand efficiency metrics. ACS Med. Chem. Lett. 2014;5(6):616-8.

Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comp. Chem. 2010;31(2):455-61.

Hess B, Kutzner C, Van Der Spoel D, Lindahl E. GROMACS 4: Algorithms for highly efficient, Load-balanced, and scalable molecular simulation. J. Chem. Theory. Comput. 2008;4(3):435-47.

Kaminski GA, Friesner RA, Tirado-Rives J, Jorgense WL. Evaluation and reparameterization of the opls-aa force field for proteins via comparison with accurate quantum chemical calculations on peptides. J. Phys. Chem. B. 2001;105: 6474−87.

Zoete V, Cuendet MA, Grosdidier A, Michielin O. SwissParam: A fast force field generation tool for small organic molecules. J. Comput. Chem. 2011;32(11): 2359-68.

Alamri MA. Pharmacoinformatics and molecular dynamic simulation studies to identify potential small-molecule inhibitors of WNK-SPAK/OSR1 signaling that mimic the RFQV motifs of WNK kinases. Arab. J. Chem. 2020;13(4):5107-17.

Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983;79(2): 926-35.

Hess B, Bekker H, Berendsen HJ, Fraaije JG. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 1997;18(12):1463-72.

Tripathi S, Kumar A, Kumar BS, Negi AS, Sharma A. Structural investigations into the binding mode of novel neolignans Cmp10 and Cmp19 microtubule stabilizers by in silico molecular docking, molecular dynamics and binding free energy calculations. J. Biomol. Struct. Dyn. 2016;34(6):1232-40.

Kenny PW. The nature of ligand efficiency. J. Cheminformatics. 2019;11(1):8.‏

Padma VV. An overview of targeted cancer therapy. Biomed. 2015;5(4):19.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin. 2011;61:69-90.

Xu G, McLeod HL. Strategies for enzyme/prodrug cancer therapy. Clin. Cancer. Res. 2001;7:3314-24.

Xie L, Bourne PE. Developing multi-target therapeutics to fine-tune the evolutionary dynamics of the cancer ecosystem. Front. Pharmacol. 2015;6:209.

Sakkiah S, Senese S, Yang Q, Lee KW, Torres JZ. Dynamic and multi-pharmacophore modeling for designing polo-box domain inhibitors. PLoS. One. 2014;9(7):e101405.

Copeland RA. Conformational adaptation in drug-target interactions and residence time. Future. Med. Chem. 2011;3(12): 1491-501.

Lu S, Liu HC, Chen YD, Yuan HL, Sun SL, Gao YP, Yang P, Zhang L, Lu T. Combined pharmacophore modeling docking and 3D-QSAR studies of PLK1 inhibitors. Int. J. Mol. Sci. 2011;12:8713-39.