• Open Access

Using Ligand-Mapping Simulations to Design a Ligand Selectively Targeting a Cryptic Surface Pocket of Polo-Like Kinase 1

Authors

  • Yaw Sing Tan,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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    • These authors contributed equally to this work.

  • Dr. Paweł Śledź,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
    2. Present address: Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried (Germany)
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    • These authors contributed equally to this work.

  • Dr. Steffen Lang,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • Christopher J. Stubbs,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • Dr. David R. Spring,

    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • Prof. Chris Abell,

    Corresponding author
    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
    • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • Dr. Robert B. Best

    Corresponding author
    1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
    • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK)
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  • We are grateful for funding from the Agency for Science, Technology and Research (Y.S.T.), the Wellcome Trust, the Gates Cambridge Trust, St. Edmund’s College (P.Ś.) and DAAD (S.L.). R.B.B. is supported by a Royal Society University Research Fellowship. We thank Dr. Marko Hyvönen for assistance with the structural biology, Dr. Chandra Verma for helpful discussions.

Abstract

original image

An explicit solvent ligand-mapping approach was used to reveal an otherwise hidden hydrophobic pocket in polo-like kinase 1 (Plk1). It predicted a novel ligand binding mode that was used for the design of a new ligand with high affinity for Plk1. X-ray crystallography confirmed that the binding was specific to the intended pocket.

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