title: Diphenylether derivative as selective inhibitor of protein tyrosine phosphatase 1B (PTP1B) over t-cell protein tyrosine phosphatase (TCPTP) identified through virtual screening.
abstract: Even though protein tyrosine phosphatase has been identified as a validated therapeutic target over a decade for type II diabetes and obesity, developing a selective inhibitor to protein tyrosine phosphatase 1B (PTP1B) over other cellular PTPases has been a complicated task owing to the highly conserved and polar nature of the PTP1B catalytic site. Virtual screening study of in-house chemical depository resulted in the prioritization of few low molecular weight compounds as PTP1B inhibitors. The in-vitro pNPP assays were carried out on prioritized compounds in both PTP1B and T-cell protein tyrosine phosphatase (TCPTP). From this we identified four low molecular weight compounds as PTP1B inhibitors, of which the compound AU-2439 has shown 5 fold selectivity towards PTP1B over highly homologous TCPTP. In this short communication selectivity of AU-2439 is explained based on interaction with critical active site residues in both proteins using docking models.
authors.affiliation: Aurigene Discovery Technology Ltd, Electronic city, Phase II, Hosur road, Bangalore-560100, India. manusekhar1975@gmail.com
authors.forename: M V V V Sekhar
authors.initials: MV
authors.lastname: Reddy
authors.forename: Chakshusmathi
authors.initials: C
authors.lastname: Ghadiyaram
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Panigrahi
authors.forename: Subramanya
authors.initials: S
authors.lastname: Hosahalli
authors.forename: Lakshmi Narasu
authors.initials: LN
authors.lastname: Mangamoori
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D045162:Thiazolidinediones / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione; C516607:PTPN1 protein, human; C516649:PTPN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2