The design strategy of selective PTP1B inhibitors over TCPTP

Li, XiangQian; Wang, Lijun; Shi, Dongxia

doi:10.1016/j.bmc.2016.06.035

Cited by 49 publications

(38 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The positions of the six clusters were mapped on the structure of PTP1B ( Figure 2 ) and included: (1) the active site [ 25 ], (2) the secondary phospho-tyrosine binding site [ 26 ], (3) a site centred on L41, (4) an allosteric binding site [ 27 , 28 ], (5) a site centred on V155, and (6) a site centred on E252. Importantly, all but two clusters (5 and 6), mapped to functionally important conserved PTP motifs [ 24 , 29 ] or to sites that have been previously identified in drug discovery [ 27 , 28 , 30 , 31 ], hence providing confidence in our approach. The additional clusters 5 and 6, mapped into new pockets not yet targeted for this enzyme, which could be explored in the future.…”

Section: Resultsmentioning

confidence: 86%

VSpipe, an Integrated Resource for Virtual Screening and Hit Selection: Applications to Protein Tyrosine Phospahatase Inhibition

et al. 2018

View full text Add to dashboard Cite

The use of computational tools for virtual screening provides a cost-efficient approach to select starting points for drug development. We have developed VSpipe, a user-friendly semi-automated pipeline for structure-based virtual screening. VSpipe uses the existing tools AutoDock and OpenBabel together with software developed in-house, to create an end-to-end virtual screening workflow ranging from the preparation of receptor and ligands to the visualisation of results. VSpipe is efficient and flexible, allowing the users to make choices at different steps, and it is amenable to use in both local and cluster mode. We have validated VSpipe using the human protein tyrosine phosphatase PTP1B as a case study. Using a combination of blind and targeted docking VSpipe identified both new and known functional ligand binding sites. Assessment of different binding clusters using the ligand efficiency plots created by VSpipe, defined a drug-like chemical space for development of PTP1B inhibitors with potential applications to other PTPs. In this study, we show that VSpipe can be deployed to identify and compare different modes of inhibition thus guiding the selection of initial hits for drug discovery.

show abstract

Section: Resultsmentioning

confidence: 86%

VSpipe, an Integrated Resource for Virtual Screening and Hit Selection: Applications to Protein Tyrosine Phospahatase Inhibition

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Among them, the A, B, and C sites ( Figure 6 ) were essential for protein function and conducted to regulate insulin signaling markers [ 16 , 33 , 34 ]. The primary phosphate-binding pocket was A site, where phosphotyrosine (pTyr) residues of the insulin receptor (IR) kinase activation peptide were dephosphorylated [ 35 ]. This pocket was not large with 10 Å width and 9 Å depth which were measured by length from Tyr46 to Gln262 and distance from Cys215 to Phe182, respectively [ 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach

Zhang

Jiang

et al. 2017

Computational and Mathematical Methods in Medicine

View full text Add to dashboard Cite

Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for treating cancer, obesity, and type 2 diabetes. In our work, the way of combined ligand- and structure-based approach was applied to analyze the characteristics of PTP1B enzyme and its interaction with competitive inhibitors. Firstly, the pharmacophore model of PTP1B inhibitors was built based on the common feature of sixteen compounds. It was found that the pharmacophore model consisted of five chemical features: one aromatic ring (R) region, two hydrophobic (H) groups, and two hydrogen bond acceptors (A). To further elucidate the binding modes of these inhibitors with PTP1B active sites, four docking programs (AutoDock 4.0, AutoDock Vina 1.0, standard precision (SP) Glide 9.7, and extra precision (XP) Glide 9.7) were used. The characteristics of the active sites were then described by the conformations of the docking results. In conclusion, a combination of various pharmacophore features and the integration information of structure activity relationship (SAR) can be used to design novel potent PTP1B inhibitors.

show abstract

“…Something interesting to highlight is that the interactions formed by the three inhibitors include important residues for the enzyme function like Gln262 and the Asp48, without having interactions with the denominated signature residues of the phosphatases (H/V)CXXGXXR(S/T) [ 34 , 68 ]. In this context, several studies have shown that selectivity against TCPTP can be achieved by interactions with residues such as Arg24, Arg47, Asp48, Arg254, Met258, and Gln262 [ 35 , 65 ]. Additionally, we investigated their binding mode in TCTPT by molecular docking, finding that the three compounds made interactions with different residues of the enzyme ( Figure S3 ).…”

Section: Resultsmentioning

confidence: 99%

“…The highly conserved catalytic site in the phosphatases family hinders the finding of a selective molecule, especially against its closest homologous T-cell protein tyrosine phosphatase (TCPTP) [ 33 , 34 ]. One strategy is to seek interactions with specific sites of the PTP1B [ 35 , 36 , 37 ]. In this sense, the enzyme has two aryl phosphate binding sites, a catalytic site with high affinity that contains the Cys215, and another one with low affinity that contains the Arg24 and Arg254.…”

Section: Introductionmentioning

confidence: 99%

Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies

et al. 2017

View full text Add to dashboard Cite

The Atlas of Diabetes reports 415 million diabetics in the world, a number that has surpassed in half the expected time the twenty year projection. Type 2 diabetes is the most frequent form of the disease; it is characterized by a defect in the secretion of insulin and a resistance in its target organs. In the search for new antidiabetic drugs, one of the principal strategies consists in promoting the action of insulin. In this sense, attention has been centered in the protein tyrosine phosphatase 1B (PTP1B), a protein whose overexpression or increase of its activity has been related in many studies with insulin resistance. In the present work, a chemical library of 250 compounds was evaluated to determine their inhibition capability on the protein PTP1B. Ten molecules inhibited over the 50% of the activity of the PTP1B, the three most potent molecules were selected for its characterization, reporting Ki values of 5.2, 4.2 and 41.3 µM, for compounds 1, 2, and 3, respectively. Docking and molecular dynamics studies revealed that the three inhibitors made interactions with residues at the secondary binding site to phosphate, exclusive for PTP1B. The data reported here support these compounds as hits for the design more potent and selective inhibitors against PTP1B in the search of new antidiabetic treatment.

show abstract

The design strategy of selective PTP1B inhibitors over TCPTP

Cited by 49 publications

References 54 publications

VSpipe, an Integrated Resource for Virtual Screening and Hit Selection: Applications to Protein Tyrosine Phospahatase Inhibition

VSpipe, an Integrated Resource for Virtual Screening and Hit Selection: Applications to Protein Tyrosine Phospahatase Inhibition

Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach

Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies

Contact Info

Product

Resources

About