title: Identification of a potent inhibitor of human dual-specific phosphatase, VHR, from computer-aided and NMR-based screening to cellular effects.
abstract: Human vaccinia H1-related phosphatase (VHR) is a dual-specific phosphatase (DSPs) that plays an important role in the mitogen-activated protein (MAP) kinase cascade regulation. It is also a potential drug target for diseases that are related to immune response. By combining a virtual and NMR-based ligand-screening strategy, we successfully identified four VHR inhibitors, of which GATPT ((glucosamine-aminoethoxy)triphenyltin) can bind to VHR with a K(i) value of 2.54 muM. The putative binding mode of GATPT was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Furthermore, we found that this compound can significantly inhibit the dephosphorylation of the extracellular regulated kinases (ERKs), and c-Jun N-terminal kinases (JNKs) and block the G(1)-S phase transition in the cell cycle. Therefore, GATPT is a promising lead structure for designing more effective inhibitors of VHR.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shi
authors.forename: Sartaj
authors.initials: S
authors.lastname: Tabassum
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Jiahai
authors.initials: J
authors.lastname: Zhang
authors.forename: Suvigya
authors.initials: S
authors.lastname: Mathur
authors.forename: Jihui
authors.initials: J
authors.lastname: Wu
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Shi
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D003198:Computer Simulation; D054640:Dual Specificity Phosphatase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D020928:Mitogen-Activated Protein Kinases; D054640:Dual Specificity Phosphatase 3