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.

Keywords: Gerotarget; PTP-MEG2 inhibitor; core hopping; diabetes; molecular dynamics simulation; selectivity.

Figure 1. ZINC01433265 derivatives with high docking scores generated by core hopping

Figure 2. Synthetic routes of compounds 4a and 4b

Figure 3. Docking of compound 4a with PTP-MEG2

a. Surface representation of PTP-MEG2 in complex with 4a. b. Docking interactions of compound 4a with PTP-MEG2 active site. The H-bond interactions between PTP-MEG2 and compound 4a are shown as red dashed lines.

Figure 4. The interaction energies of top 10 pairwise residues of the complex formed by PTP-MEG2 (red), PTP1B (blue), and TCPTP (purple) with compound 4a