title: Design and synthesis of a dimeric derivative of RK-682 with increased inhibitory activity against VHR, a dual-specificity ERK phosphatase: implications for the molecular mechanism of the inhibition.
abstract: BACKGROUND
  VHR is a dual-specificity phosphatase, which dephosphorylates activated ERK1/2 and weakens the ERK signaling cascade in mammalian cells. A selective inhibitor is expected to be useful for revealing the physiological function of VHR.
  
  
  RESULTS
  First, we investigated the molecular mechanism of VHR inhibition by a known natural product, RK-682. Kinetic analysis indicated that inhibition was competitive toward the substrate, and two molecules of RK-682 were required to inhibit one molecule of VHR. Based on the structure-activity relationships for VHR inhibition by RK-682 derivatives, we constructed a binding model using molecular dynamics calculation. Based on this model, we designed and synthesized a novel dimeric derivative. As expected, the dimeric derivative showed increased inhibition of VHR, supporting our proposed mechanism of VHR inhibition by RK-682.
  
  
  CONCLUSIONS
  We have developed a novel inhibitor of VHR based on the results of kinetic analysis and docking simulation.
authors.affiliation: Antibiotics Laboratory, RIKEN, Hirosawa, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Usui
authors.forename: S
authors.initials: S
authors.lastname: Kojima
authors.forename: S
authors.initials: S
authors.lastname: Kidokoro
authors.forename: K
authors.initials: K
authors.lastname: Ueda
authors.forename: H
authors.initials: H
authors.lastname: Osada
authors.forename: M
authors.initials: M
authors.lastname: Sodeoka
mesh_terms: D019281:Dimerization; D015195:Drug Design; D054640:Dual Specificity Phosphatase 3; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D010749:Phosphoprotein Phosphatases / Q000032:analysis* / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C094097:RK 682; D010749:Phosphoprotein Phosphatases; D054640:Dual Specificity Phosphatase 3; D017027:Protein Tyrosine Phosphatases