Identification of inhibitors that target dual-specificity phosphatase 5 provide new insights into the binding requirements for the two phosphate pockets

Conclusions:
The new DUSP5 inhibitors we identify in this study typically have sulfonates 7 Å apart, likely positioning them where the two phosphates of the substrate peptide (pThr-Glu-pTyr) bind, with one inhibitor also positioning a phenolic hydroxyl where the water nucleophile may reside. Polysulfonated aromatic compounds do not commonly appear in drugs and have a tendency to aggregate. One FDA-approved polysulfonated drug, suramin, inhibits DUSP5 and also aggregates. Docking and modeling studies presented herein identify polysulfonated aromatic inhibitors that do not aggregate, and provide insights to guide future design of mimics of the dual-phosphate loops of the ERK substrates for DUSPs.

Source: BMC Biochemistry - August 19, 2015 Category: Biochemistry Authors: Terrence NeumannElise SpanKelsey KalousRobert BongardAdam GastonguayMichael LepleyRaman KuttyJaladhi NayakChris BohlRachel LangeMajher SarkerMarat TalipovRajendra RathoreRamani RamchandranDaniel Sem Source Type: research