Virtual Screening and Biochemical Evaluation to Identify the Allosteric Inhibitors of Dual Specificity Phosphatase 1

Abstract

Although a wealth of persuasive evidence was provided for the involvement of dual specificity phosphatase 1 (DUSP1) in cancers, depression, and hepatitis C virus replication, small-molecule inhibitors have been reported rarely. Because most competitive phosphatase inhibitors are disadvantageous in terms of pharmacological properties due to the possession of highly polar groups, we aim in this work to identify the allosteric DUSP1 inhibitors through the structure-based virtual screening. Using the modified protein-ligand binding energy function involving an accurate molecular dehydration term, we identify six allosteric DUSP1 inhibitors that impair the enzymatic activity at low-micromolar level. Consistent with the kinetic analysis on the inhibitory mechanism, docking simulation results indicate that the newly discovered inhibitors would bind in the peripheral binding pocket of DUSP1 in preference to the active site. Besides the micromolar-level biochemical potency, the allosteric DUSP1 inhibitors found in this work may be meritorious over the competitive ones because of the lack of the reactive moiety to mimic the substrate phosphate group. Hence, they are anticipated to serve as a good starting point for the development of new therapeutics against cancers and neurological diseases.