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.
Chem Biol
; 8(12): 1209-20, 2001 Dec.
Article
in En
| MEDLINE
| ID: mdl-11755399
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.CONCLUSION:
We have developed a novel inhibitor of VHR based on the results of kinetic analysis and docking simulation.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Design
/
Protein Tyrosine Phosphatases
/
Phosphoprotein Phosphatases
/
Enzyme Inhibitors
Language:
En
Journal:
Chem Biol
Journal subject:
BIOLOGIA
/
BIOQUIMICA
/
QUIMICA
Year:
2001
Document type:
Article
Affiliation country:
Japan