Discovery of Novel DUSP16 Phosphatase Inhibitors through Virtual Screening with Homology Modeled Protein Structure

Abstract

Recently, dual-specificity phosphatase 16 (DUSP16) emerged as a promising therapeutic target protein for the development of anti-atherosclerosis and anticancer medicines. The present study was undertaken to identify the novel inhibitors of DUSP16 based on the structure-based virtual screening. We have been able to find seven novel inhibitors of DUSP16 through the drug design protocol involving homology modeling of the target protein, docking simulations between DUSP16 and its putative inhibitors with the modified scoring function, and in vitro enzyme assay. These inhibitors revealed good potency, with IC 50 values ranging from 1 to 22 µM, and they were also screened computationally for having desirable physicochemical properties as drug candidates. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory activity against DUSP16. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of DUSP16 are addressed in detail.

Discovery of Dual Inhibitors for Wild Type and D816V Mutant of c-KIT Kinase through Virtual and Biochemical Screening of Natural Products

“…In recent years, a potential-based scoring function implementing a sophisticated molecular solvation free energy term was proposed and validated on the basis of the extended solvent-contact model . The outperformance of this new scoring function was demonstrated in estimating the biochemical potencies of inhibitors of various target enzymes. , We demonstrate that virtual screening with a modified scoring function is useful for enriching chemical libraries with natural products that have good inhibitory activity against c-KIT.…”

Docking‐based In Silico Screening for Identification of Micromolar Inhibitors of Tropomyosin‐related Kinase A from Natural Origin

“…Recently, a potential‐based scoring function involving a proper molecular hydration term constructed on the basis of the extended solvent‐contact model has been proposed and validated . The outperformance of this protein–ligand binding free energy function was justified by successfully reproducing the experimentally determined biochemical potencies of the known inhibitors with respect to various target proteins . In this study, we aim to show that the molecular docking‐based virtual screening through the enhanced scoring function is appropriate for extending the library of chemicals with novel TrkA inhibitors of natural origin.…”

“…The calculations of atomic charges through the Gasteiger–Marsilli method then followed. The modified AutoDock program was employed for virtual screening of the ATP‐competitive TrkA inhibitors because it had been appreciated in a variety of target proteins that its ligand–protein binding free energy function shows the excellent performance …”

New Approaches to Difficult Drug Targets: The Phosphatase Story

“…50 As outlined below, however, interesting small-molecule PTP inhibitors are emerging from the use of traditional high-throughput screening methods, 51,52 and these chemotypes could form the foundation for new chemical libraries with a higher success rate. Computational screening with large virtual chemical libraries, especially when coupled with high-throughput wet-bench laboratory screening, has also generated some interesting small-molecule inhibitors, [53][54][55][56][57][58][59][60][61][62] which could nucleate future libraries. Alternative strategies for the identification of small-molecule PTP inhibitors have included assays that are formatted to use cells, whole organisms, or computational methods.…”