1T49

• Allosteric Inhibition of Protein Tyrosine Phosphatase 1B

• Reference:

Methods

• Structure-based Virtual Screening- UNITY for 1st screening of database from ‘Zinc’, Lead-Quest (4,850).- FlexS for flexible superposition of ligands.- FlexX for flexible docking.(139)- These modules are included in the SYBYL version 8.1 software (Tripos Inc.)

Structure-Based Virtual Screening

3rd filtering:Flexible docking and scoring

by FlexX / CScore

2nd filtering:

Flexible superposition by FlexS

Template ; Lobaric acid

1st filtering by Unity 3D Search:queries based on the PTP1B structure

(PDB id= 1T49)

Query used to Unity 3D search for PTP1B-selective inhibitor. Magenta ligand is the reported PTP1B inhibitor

A Drug-enzyme Binding Model

Changon Seo et al., 2009

Christian Wiesmann et al., 2004

Noncompetitive Inhibitors of PTP1B

Docking Modes of Active Compounds into Allosteric Site

Compound 1 (Lobaric acid)

Compound 1 (Carboxylate form)

Compound 2

Compound 3 Compound 8 Compound 9

Active Ligands by Flexible Superposi-tion

1. Benzene ring interacting with Phe280

2. H-bonding with Asn1933. Two hydrophobic alkyl chains

An Active Ligand inhibiting PTP1B activity

Zinc 7589409(Score: -21.633)

Hydrophobicity Potential (PDB id: 1T49)

Lobaric acid(Score: -19.908)

References

• Changon Seo, Jae Hak Sohn, Jong Seog Ahn, Joung Han Yim, Hong Kum Lee, Hyuncheol Oh (2009) Protein tyrosine phosphatase 1B inhibitory effects of depsidone and pseudodepsidone metabolites from the Antarctic lichen Stereocaulon alpinum, Bioorganic & Medicinal Chemistry Letters 19 2801–2803

• Christian Wiesmann, Kenneth J Barr, Jenny Kung, Jiang Zhu, Daniel A Erlanson, Wang Shen, Bruce J Fahr, Min Zhong, Lisa Taylor, Mike Randal, Robert S McDowell & Stig K Hansen (2004) Allosteric in-hibition of protein tyrosine phosphatase 1B, Na-ture Structural & Molecular Biology  11, 730 - 737