title: Virtual screening, optimization, and identification of a novel specific PTP-MEG2 Inhibitor with potential therapy for T2DM.
abstract: Megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) is a tyrosine phosphatase expressed in megakaryocytic cells, and causes insulin sensitization when down regulated. Therefore, specific inhibitors of PTP-MEG2 are potential candidates for novel Type 2 Diabetes (T2DM)therapy. In this study, we discovered PTP-MEG2 inhibitors using high throughput and virtual screening (HTS/VS) and structural optimization in silicon.Eight compound-candidates were identified from the interactions with PTP-MEG2, protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP). Results from enzymatic assays show compounds 4a and 4b inhibited PTP-MEG2 activity with an IC50 of 3.2 μM and 4.3 μM, respectively. Further, they showed a 7.5 and 5.5 fold change against PTP1B and TCPTP, respectively. We propose compounds 4a and 4b are PTP-MEG2 inhibitors with potential therapeutic use in T2DM treatment.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China.|Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.affiliation: Tianjin Medical University Eye Hospital, Tianjin, China.
authors.forename: Xiubo
authors.initials: X
authors.lastname: Chen
authors.affiliation: Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors.forename: Weiren
authors.initials: W
authors.lastname: Xu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China.
authors.forename: Runling
authors.initials: R
authors.lastname: Wang
mesh_terms: D003924:Diabetes Mellitus, Type 2; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008533:Megakaryocytes / Q000201:enzymology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases
keywords: Gerotarget; PTP-MEG2 inhibitor; core hopping; diabetes; molecular dynamics simulation; selectivity