title: 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 IC50 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.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea hspark@sejong.ac.kr ryuse@hanyang.ac.kr.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Bioengineering, Hanyang University, Seoul, Korea.
authors.forename: So Ya
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Electronic Engineering, Hanyang University, Seoul, Korea.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Nam
authors.affiliation: Department of Bioengineering, Hanyang University, Seoul, Korea.
authors.forename: Seong Eon
authors.initials: SE
authors.lastname: Ryu
mesh_terms: D020134:Catalytic Domain; D015195:Drug Design; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D054639:Mitogen-Activated Protein Kinase Phosphatases; C439065:DUSP16 protein, human; D054637:Dual-Specificity Phosphatases
keywords: cheminformatics; computational chemistry; enzyme assays; medicinal chemistry