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

Abstract

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.

Enhancing polo-like kinase 1 selectivity of polo-box domain-binding peptides

“…Abell has also shown that the same cryptic pocket can be accessed by the phenyl ring of the terminal Phe residue in the longer PBIP1 pT78-derived sequence FDPPLHSpTA 15 and by the phenyl ring of 3-phenylpropylamide on the Pro residue of 1 . 16 This group has also shown that higher affinity can be realized by replacing the terminal Phe residue in the FDPPLHSpTA sequence with a residue that contains a more lipophilic 2-benzothiophene ring ( 5 ), which is consistent with the highly lipophilic nature of the cryptic pocket (Figure 1). 17 …”

Stapled peptide design: principles and roles of computation

“…The positions sampled by the benzene probes during the simulations are then converted into occupancy maps that are represented by density grids. Such simulations have been successfully used to identify a novel ligand-binding mode at a cryptic binding pocket [83], enhance conformational sampling, and locate hydrophobic peptide binding sites [82,84]. The method was tested on five proteins that have known hydrocarbon staple interaction sites.…”

Application of oxime-diversification to optimize ligand interactions within a cryptic pocket of the polo-like kinase 1 polo-box domain

“…The Plk1 PBD is remarkable by its inclusion of a hydrophobic “cryptic binding pocket” formed by Y417, Y421, Y481, F482, Y485 and L478, which is revealed by a more than 100° rotation of the Y481 side chain in the presence of ligands capable of accessing the pocket. 4 Many efforts to develop PBD-binding antagonists have utilized peptides based on the region of the polo-box domain interacting protein 1 (PBIP1) proximal to the phosphorylated pT78 residue. 5 Using the PBIP1 pT78-derived sequence, FDPPLHSpTA, Sledz et al have shown that the N -terminal Phe residue can access this pocket, 6 and that replacing the Phe residue with a variety of arylpropyl amides can improve binding affinities.…”