Identification of Two Novel VHR Phosphatase Inhibitors with Structure-Based Virtual Screening
Hwang-Seo Park, Jeong-Yi Jeon, Dae-Gwin Jeong, Seong-Eon Ryu
Bulletin of the Korean Chemical Society (Print)
Protein tyrosine phosphatases (PTPs) are a family of the regulatory enzymes that are responsible for the dephosphorylation of phosphotyrosine residues in the protein substrates. A series of experimental evidence has been reported so far to support the correlation between malfunctions in PTP activity and various diseases including cancer, neurological disorders, and diabetes. 1 This has made PTPs be a promising target for drug discovery. Of the various PTPs, vaccinia H1-related (VHR) phosphatase
... belongs to a dual-specificity phosphatase (DSP) and dephosphorylates the activated ERK and JNK MAP kinases, which has an effect of weakening the ERK signaling cascade in mammalian cells. 2, 3 It has been known that the human VHR phosphatase would be involved in the regulation of cell-cycle progression and modulated during the cell cycle. 4 Also, the cells lacking VHR were shown to be arrested at the G1-S and G2-M transitions of the cell cycle with a decreased telomerase activity. This indicates that VHR can serve as a therapeutic target for cancer. Furthermore, the VHR activity has been known to related with the immune response of the activated T cells 5 and vaccinia-related kinase 3 (VRK3). 6 The involvement of VHR in immune response further motivates the discovery of small-molecule ligands to regulate its activity. A conserved structural scaffold for both DSPs and PTPs was observed in the X-ray crystal structure of VHR. 7 Its shallow active site pocket is consistent with the broad substrate specificity for phosphorylated serine, threonine, and tyrosine residues. The presence of the positively charged crevices near the active site can be invoked to explain the preference of VHR for the substrates with two phosphorylated residues. The catalytic residue (Cys124) resides in close proximity to the central sulfur atom of the substrate analogue in the crystal structure at a distance of 3.65 Å. This implies that Cys124 acts as a nucleophile attacking the central phosphorus atom of a substrate to form a phosphoenzyme intermediate. 8 It was also shown in the X-ray crystal structure that the substrate analogue should be stabilized in the active site through the formation of multiple hydrogen bonds with Arg130. These structural features provide useful information for designing the small-molecules inhibitors of VHR. However, only a few classes of VHR inhibitors have been discovered so far. 9-15 a These two authors contribute equally to this work.