Virtual screening, optimization, and identification of a novel specific PTP-MEG2 Inhibitor with potential therapy for T2DM
| Autor: | Xiaobo Li, Xiu-Bo Chen, Meiyan Wang, Runling Wang, Lei Dong, Wei-Ren Xu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
PTP-MEG2 inhibitor
0301 basic medicine Gerontology animal structures T-Cell Protein Tyrosine Phosphatase Drug Evaluation Preclinical Protein tyrosine phosphatase Pharmacology 010402 general chemistry environment and public health 01 natural sciences Enzymatic Assays 03 medical and health sciences Research Paper: Gerotarget (Focus on Aging) Humans Medicine core hopping Enzyme Inhibitors Pharmaceutical sciences Virtual screening diabetes Gerotarget business.industry Drug discovery selectivity Protein Tyrosine Phosphatase 1B 0104 chemical sciences enzymes and coenzymes (carbohydrates) molecular dynamics simulation 030104 developmental biology Diabetes Mellitus Type 2 Oncology Protein Tyrosine Phosphatases business Megakaryocytes |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.10341 |
| Popis: | // Meiyan Wang 1,* , Xiaobo Li 1,2,* , Lei Dong 2,* , Xiubo Chen 3 , Weiren Xu 4 and Runling Wang 1 1 Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China 2 Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA 3 Tianjin Medical University Eye Hospital, Tianjin, China 4 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, China * These authors have contributed equally to this work Correspondence to: Runling Wang, email: // Keywords : PTP-MEG2 inhibitor; core hopping; diabetes; selectivity; molecular dynamics simulation; Gerotarget Received : March 22, 2016 Accepted : June 03, 2016 Published : June 30, 2016 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|