Research Papers: Gerotarget (Focus on Aging):
Virtual screening, optimization, and identification of a novel specific PTP-MEG2 Inhibitor with potential therapy for T2DM
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Meiyan Wang1,*, Xiaobo Li1,2,*, Lei Dong2,*, Xiubo Chen3, Weiren Xu4 and Runling Wang1
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
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
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.
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