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. 2010;1(3):110-114.
doi: 10.1021/ml100020e.

Exploring Potential Binding Modes of Small Drug-like Molecules to the Polo-Box Domain of Human Polo-like Kinase 1

Chenzhong Liao  1 , Jung-Eun Park, Jeong Kyu Bang, Marc C Nicklaus, Kyung S Lee
Affiliations

Exploring Potential Binding Modes of Small Drug-like Molecules to the Polo-Box Domain of Human Polo-like Kinase 1

Chenzhong Liao et al. ACS Med Chem Lett. 2010.

Abstract

Purpurogallin (PPG) and Poloxin have been reported as inhibitors of the polo-box domain (PBD) of human polo-like kinase 1 (Plk1). However, our experimental results demonstrated that PPG, but not Poloxin, binds to the phospho-binding pocket of the PBD, suggesting that their modes of PBD inhibition are distinct. Induced fit docking (IFD) analyses led us to propose that PPG fills the SpT pocket via pi-pi stacking and hydrogen bonding interactions, thus providing a rationale for designing novel PBD inhibitors. In contrast, Poloxin may fill a different site present near the SpT pocket by forming a covalent bond with a nucleophilic Cys residue.

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Figures

Figure 1
Figure 1
The binding mode of PLHSpT with the Plk1 PBD.
Figure 2
Figure 2
Structures of compounds 1−4.
Figure 3
Figure 3
Inhibition of Plk1 PBD binding by PLHSpT, PLHST, PPG, and poloxin. O.D., optical density.
Figure 4
Figure 4
Microspecies distribution of PPG calculated by Marvin 5.1.4.
Figure 5
Figure 5
Proposed binding mode of PPG to the Plk1 PBD generated by Schrödinger's IFD protocol (see the text for details).
Figure 6
Figure 6
Binding nature of poloxin and thymoquinone to the Plk1 PBD. (A) Pocket #1 identified by SiteMap 2.3. (B) Proposed mechanisms of PBD inhibition by poloxin and thymoquinone. (C and D) Proposed binding modes of poloxin (C) and thymoquinone (D).
See this image and copyright information in PMC

References

    1. Archambault V.; Glover D. M. Polo-like kinases: Conservation and divergence in their functions and regulation. Nat. Rev. Mol. Cell. Biol. 2009, 10, 265–275. - PubMed
    1. Strebhardt K.; Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat. Rev. Cancer 2006, 6, 321–330. - PubMed
    1. Luo J.; Emanuele M. J.; Li D.; Creighton C. J.; Schlabach M. R.; Westbrook T. F.; Wong K. K.; Elledge S. J. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 2009, 137, 835–848. - PMC - PubMed
    1. Sur S.; Pagliarini R.; Bunz F.; Rago C.; Diaz L. A. Jr.; Kinzler K. W.; Vogelstein B.; Papadopoulos N. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc. Natl. Acad. Sci. 2009, 106, 3964–3969. - PMC - PubMed
    1. Lee K. S.; Idle J. R. Pinning down the polo-box domain. Chem. Biol. 2008, 15, 415–416. - PubMed