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Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors

DOI: 10.3390/ijms12128713

Keywords: PLK1, 3D-QSAR, pharmacophore, molecular docking

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Polo-like kinase 1, an important enzyme with diverse biological actions in cell mitosis, is a promising target for developing novel anticancer drugs. A combined molecular docking, structure-based pharmacophore modeling and three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a set of 4,5-dihydro-1 H-pyrazolo[4,3- h]quinazoline derivatives as PLK1 inhibitors. The common substructure, molecular docking and pharmacophore-based alignment were used to develop different 3D-QSAR models. The comparative molecular field analysis (CoMFA) and comparative molecule similarity indices analysis (CoMSIA) models gave statistically significant results. These models showed good q 2 and r 2 pred values and revealed a good response to test set validation. All of the structural insights obtained from the 3D-QSAR contour maps are consistent with the available crystal structure of PLK1. The contour maps obtained from the 3D-QSAR models in combination with the structure based pharmacophore model help to better interpret the structure-activity relationship. These satisfactory results may aid the design of novel PLK1 inhibitors. This is the first report on 3D-QSAR study of PLK1 inhibitors.


[1]  Lowery, D.M.; Lim, D.; Yaffe, M.B. Structure and function of Polo-like kinases. Oncogene 2005, 24, 248–259.
[2]  de Carcer, G.; Escobar, B.; Higuero, A.M.; Garcia, L.; Anson, A.; Perez, G.; Mollejo, M.; Manning, G.; Melendez, B.; Abad-Rodriguez, J.; et al. Plk5, a polo box domain-only protein with specific roles in neuron differentiation and glioblastoma suppression. Mol. Cell. Biol 2011, 31, 1225–1239.
[3]  Degenhardt, Y.; Lampkin, T. Targeting Polo-like kinase in cancer therapy. Clin. Cancer Res 2010, 16, 384–389.
[4]  Strebhardt, K.; Ullrich, A. Targeting polo-like kinase 1 for cancer therapy. Nat. Rev. Cancer 2006, 6, 321–330.
[5]  Strebhardt, K. Multifaceted polo-like kinases: Drug targets and antitargets for cancer therapy. Nat. Rev. Drug Discov 2010, 9, 643–660.
[6]  Cogswell, J.P.; Brown, C.E.; Bisi, J.E.; Neill, S.D. Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function. Cell Growth Differ 2000, 11, 615–623.
[7]  Petronczki, M.; Glotzer, M.; Kraut, N.; Peters, J.M. Polo-like kinase 1 triggers the initiation of cytokinesis in human cells by promoting recruitment of the RhoGEF Ect2 to the central spindle. Dev. Cell 2007, 12, 713–725.
[8]  Kotani, S.; Tugendreich, S.; Fujii, M.; Jorgensen, P.M.; 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, 371–380.
[9]  Qian, Y.W.; Erikson, E.; Li, C.; Maller, J.L. Activated polo-like kinase Plx1 is required at multiple points during mitosis in Xenopus laevis. Mol. Cell. Biol 1998, 18, 4262–4271.
[10]  Smits, V.A.; Klompmaker, R.; Arnaud, L.; Rijksen, G.; Nigg, E.A.; Medema, R.H. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat. Cell Biol 2000, 2, 672–676.
[11]  Dai, W.; Wang, Q.; Traganos, F. Polo-like kinases and centrosome regulation. Oncogene 2002, 21, 6195–6200.
[12]  Burkard, M.E.; Randall, C.L.; Larochelle, S.; Zhang, C.; Shokat, K.M.; Fisher, R.P.; Jallepalli, P.V. Chemical genetics reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells. Proc. Natl. Acad. Sci. USA 2007, 104, 4383–4388.
[13]  Moshe, Y.; Boulaire, J.; Pagano, M.; Hershko, A. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc. Natl. Acad. Sci. USA 2004, 101, 7937–7942.
[14]  Steegmaier, M.; Hoffmann, M.; Baum, A.; Lenart, P.; Petronczki, M.; Krssak, M.; Gurtler, U.; Garin-Chesa, P.; Lieb, S.; Quant, J.; et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr. Biol 2007, 17, 316–322.
[15]  Elez, R.; Piiper, A.; Kronenberger, B.; Kock, M.; Brendel, M.; Hermann, E.; Pliquett, U.; Neumann, E.; Zeuzem, S. Tumor regression by combination antisense therapy against Plk1 and Bcl-2. Oncogene 2003, 22, 69–80.
[16]  Spankuch-Schmitt, B.; Wolf, G.; Solbach, C.; Loibl, S.; Knecht, R.; Stegmuller, M.; von Minckwitz, G.; Kaufmann, M.; Strebhardt, K. Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells. Oncogene 2002, 21, 3162–3171.
[17]  Takai, N.; Hamanaka, R.; Yoshimatsu, J.; Miyakawa, I. Polo-like kinases (Plks) and cancer. Oncogene 2005, 24, 287–291.
[18]  Beria, I.; Bossi, R.T.; Brasca, M.G.; Caruso, M.; Ceccarelli, W.; Fachin, G.; Fasolini, M.; Forte, B.; Fiorentini, F.; Pesenti, E.; et al. NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor. Bioorg. Med. Chem. Lett 2011, 21, 2969–2974.
[19]  McInnes, C.; Wyatt, M.D. PLK1 as an oncology target: Current status and future potential. Drug Discov. Today 2011, 16, 619–625.
[20]  Beria, I.; Ballinari, D.; Bertrand, J.A.; Borghi, D.; Bossi, R.T.; Brasca, M.G.; Cappella, P.; Caruso, M.; Ceccarelli, W.; Ciavolella, A.; et al. Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors. J. Med. Chem 2010, 53, 3532–3551.
[21]  Beria, I.; Valsasina, B.; Brasca, M.G.; Ceccarelli, W.; Colombo, M.; Cribioli, S.; Fachin, G.; Ferguson, R.D.; Fiorentini, F.; Gianellini, L.M.; et al. 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazolines as potent and selective Polo-like kinase 1 (PLK1) inhibitors. Bioorg. Med. Chem. Lett 2010, 20, 6489–6494.
[22]  Keppner, S.; Proschak, E.; Schneider, G.; Spankuch, B. Identification and validation of a potent type II inhibitor of inactive polo-like kinase 1. ChemMedChem 2009, 4, 1806–1809.
[23]  Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc 1988, 110, 5959–5967.
[24]  Klebe, G.; Abraham, U.; Mietzner, T. Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J. Med. Chem 1994, 37, 4130–4146.
[25]  , version 6.9. Users’ Manual; Tripos, Inc.: St. Louis, MO, USA, 2002.
[26]  Fernandez, A.; Sanguino, A.; Peng, Z.; Crespo, A.; Ozturk, E.; Zhang, X.; Wang, S.; Bornmann, W.; Lopez-Berestein, G. Rational drug redesign to overcome drug resistance in cancer therapy: Imatinib moving target. Cancer Res 2007, 67, 4028–4033.
[27]  Wu, G.; Robertson, D.H.; Brooks, C.L., III; Vieth, M. Detailed analysis of grid-based molecular docking: A case study of CDOCKER—A CHARMm-based MD docking algorithm. J. Comput. Chem 2003, 24, 1549–1562.
[28]  , version 2.5. Help Topics; Accelrys Inc.: San Diego, CA, USA, 2009.
[29]  Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol 1997, 267, 727–748.
[30]  , version 5.0 User Guide; CCDC Software Ltd.: Cambridge, UK, 2010.
[31]  Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem 2004, 47, 1739–1749.
[32]  , version 4.5 User Manual; Schr?dinger, LLC: New York, NY, USA, 2007.
[33]  Leach, A.R.; Gillet, V.J.; Lewis, R.A.; Taylor, R. Three-dimensional pharmacophore methods in drug discovery. J. Med. Chem 2010, 53, 539–558.
[34]  Wolber, G.; Langer, T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Model 2004, 45, 160–169.


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