The development of potent non-peptidic PTP-1B inhibitors

Dufresne, Claude; Roy, Patrick; Wang, Zhaoyin; Asante‐Appiah, Ernest; Cromlish, Wanda; Boie, Yves; Forghani, Farnaz; Desmarais, Sylvie; Wang, Qingping; Skorey, Kathryn; Waddleton, Deena; Ramachandran, Chidambaram; Kennedy, Brian P.; Xu, Lijing; Gordon, Robert J.; Chan, Chi Chung; Leblanc, Yves

doi:10.1016/j.bmcl.2003.11.048

Cited by 68 publications

(42 citation statements)

References 28 publications

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“…Ligands that bind to the D site are also responsible for a wide range of increases in potency. For example, bromine and chlorine attached ortho to the phosphonate on the aryl ring of pF 2 PMP increase potency by about 5-and 16-fold, respectively (27), and o-carboxyl attached to a 2-carboxymethoxybenzoic acid derivative increases potency by 130-fold (28). Finally, two ligands that bind at the A-E border, the side chain of Arg 1164 of the IR kinase activation peptide (20), and the indole ring of a 2-(oxalyl-amino)-thiophene-3-carboxylic acid derivative (29), interact with Phe 182 of the flap through -stacking interactions; their contributions to binding, however, have not been reported.…”

Section: Resultsmentioning

confidence: 99%

“…These interactions not only explain the high potency of the trifluoro derivative but also the loss of activity when fluorines are replaced with nonpolar substituents. Apart from the obvious loss of electrostatic interactions, replacing a single fluorine with methyl (25) or phenyl (26) or replacing the entire trifluoro group with an isopropyl (27) probably causes varying degrees of steric clash with Arg 47 . In the latter case, potency can be partially recovered but only after significantly increasing molecular weight by replacing the isopropyl with phenethyl (28), which probably interacts with the hydrophobic region of Arg 47 .…”

mentioning

confidence: 99%

“…Design and SAR of D Site Substituents-Halides and small linear substituents attached ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl template were synthesized first because o-Br had been reported to increase the activity of DFMP derivatives by 5-16-fold (27). The IC 50 value for the unsubstituted IZD benzimidazole aryl sulfonamide 36 is 120 nM; o-CN, -F, -CH 3 , -Cl, -acetylene, and -Br substituents increase potency by 3.9-, 3.5-, 2-, 1.6-, 1-, and 0.7-fold, respectively ( Table 5).…”

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confidence: 99%

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Structural Insights into the Design of Nonpeptidic Isothiazolidinone-containing Inhibitors of Protein-tyrosine Phosphatase 1B

Paul

Gonneville

Hillman

et al. 2006

Journal of Biological Chemistry

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Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp 48 , and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp 48 and the backbone NH of Arg 47 via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe 182 of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular -stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail.Type II diabetes, also known as non-insulin-dependent diabetes mellitus, is characterized by a deficiency in insulin signaling despite normal or greatly elevated levels of insulin. Although the cause of insulin resistance is unknown, inhibiting enzymes that negatively regulate the signaling pathway may restore insulin responsiveness. Protein-tyrosine phosphatase 1B (PTP1B), 2 a key negative regulator of insulin signaling, has emerged as an attractive target for the treatment of type II diabetes. PTP1B directly inactivates the insulin receptor (IR) by dephosphorylating tyrosine residues in the regulatory domain (1, 2) and its overexpression inhibits IR signaling (3). The most convincing evidence for its potential use as a therapeutic target, however, is that PTP1B knock-out mice (4) and those injected with an antisense oligonucleotide (5, 6) displayed increased insulin sensitivity.A number of PTP1B inhibitors containing highly charged non-hydrolyzable phosphonate mimetics have been reported (7-13). Poor membrane permeability, however, has limited their development as drug candidates. The lack of inhibitors with suitable physicochemical properties can be attributed to the need to interact with the highly positively charged primary phosphate binding pocket and the surrounding flat, solventexposed region.We have recently reported the structure-based design of a novel isothiazolidino...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Structural Insights into the Design of Nonpeptidic Isothiazolidinone-containing Inhibitors of Protein-tyrosine Phosphatase 1B

Paul

Gonneville

Hillman

et al. 2006

Journal of Biological Chemistry

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“…All other inhibitors were synthesized at Merck Frosst Canada Ltd., and the methods of synthesis have been described (10,11,14).…”

Section: Methodsmentioning

confidence: 99%

Residues Distant from the Active Site Influence Protein-tyrosine Phosphatase 1B Inhibitor Binding

Montalibet

Skorey²,

McKay

et al. 2006

Journal of Biological Chemistry

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Regions of protein-tyrosine phosphatase (PTP) 1B that are distant from the active site yet affect inhibitor binding were identified by a novel library screen. This screen was based on the observation that expression of v-Src in yeast leads to lethality, which can be rescued by the coexpression of PTP1B. However, this rescue is lost when yeast are grown in the presence of PTP1B inhibitors. To identify regions of PTP1B (amino acids 1-400, catalytic domain plus 80-amino acid C-terminal tail) that can affect the binding of the difluoromethyl phosphonate (DFMP) inhibitor 7-bromo-6-difluoromethylphosphonate 3-naphthalenenitrile, a library coexpressing PTP1B mutants and v-Src was generated, and the ability of yeast to grow in the presence of the inhibitor was evaluated. PTP1B inhibitor-resistant mutations were found to concentrate on helix ␣7 and its surrounding region, but not in the active site. No resistant amino acid substitutions were found to occur in the C-terminal tail, suggesting that this region has little effect on active-site inhibitor binding. An in-depth characterization of a resistant substitution localizing to region ␣7 (S295F) revealed that this change minimally affected enzyme catalytic activity, but significantly reduced the potency of a panel of structurally diverse DFMP PTP1B inhibitors. This loss of inhibitor potency was found to be due to the difluoro moiety of these inhibitors because only the difluoro inhibitors were shifted. For example, the inhibitor potency of a monofluorinated or non-fluorinated analog of one of these DFMP inhibitors was only minimally affected. Using this type of library screen, which can scan the nearly full-length PTP1B sequence (catalytic domain and C-terminal tail) for effects on inhibitor binding, we have been able to identify novel regions of PTP1B that specifically affect the binding of DFMP inhibitors.A traditional approach to understanding the structural interactions between an inhibitor and enzyme is through crystallographic studies of the inhibitor-enzyme complex. Solving the three-dimensional structure of such complexes can identify the key residues that interact with the inhibitor, providing an understanding of the mechanism of inhibition. This is normally accompanied by site-directed mutagenesis of the interacting residues to validate their role in inhibitor binding and to determine the degree to which this interaction contributes to inhibitor potency. Such structures are also important in drug design, as they allow the identification of potential interactions that could improve inhibitor potency using further chemical modifications.Protein-tyrosine phosphatase (PTP) 3 1B (EC 3.1.3.48), a potential drug target for the treatment of diabetes and obesity (1, 2), has had a number of published inhibitor-enzyme complexes, and the determinants required for the binding of various inhibitors have been identified. Because these inhibitors all target the active site, the determinants identified are located in the active-site region. Fig. 4).Because of the static nature...

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“…The hydrophobic property is critical for the chemical's cell permeability and enhanced by creating compounds that target allosteric binding site (Site-C) with reduced negative charge [7] [8].…”

Section: Introductionmentioning

confidence: 99%

Study on the Interactions of Two Isomer Selaginellins as Novel Small Molecule Inhibitors Targeting PTP1B by Docking and Molecular Dynamics Simulations

Wang¹,

Wang²,

Meng³

et al. 2018

OALib

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Protein Tyrosine Phosphatase 1B (PTP1B) plays a key role in down-regulation of insulin and leptin signaling pathways. Therefore, development of novel inhibitors of PTP1B has becoming research focus in reducing blood sugar levels for Diabetes Mellitus and Obesity. Hence, we selected two isomer Selaginellins (1 and 2) to explain and analyze the binding mechanism of the two potential inhibitors against the PTP1B by molecule docking and molecular dynamics simulations. Firstly, the two isomers (1 and 2) and the initial ligand 19 were docked to the receptor of PTP1B by using molecular docking technology. Secondly, taken the 19 as an indicator, molecular dynamic (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) methods were requested to assess the binding affinity and complex stability of the two chemicals towards PTP1B. Finally, we explained that the interactions of compound 1 and 2 take up the active binding site PTP1B. Simultaneously, energy decomposition analysis recognized several amino acid residues situated in substrate-binding site that might provide clues for future inhibitor exploitation towards PTP1B. In conclusion, these results may explain the reasons of differences of optical isomer biological activity and provide valuable information for developing novel inhibitors targeting PTP1B-mediated glucose transport and metabolism for Diabetes Mellitus and Obesity therapeutics.

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The development of potent non-peptidic PTP-1B inhibitors

Cited by 68 publications

References 28 publications

Structural Insights into the Design of Nonpeptidic Isothiazolidinone-containing Inhibitors of Protein-tyrosine Phosphatase 1B

Structural Insights into the Design of Nonpeptidic Isothiazolidinone-containing Inhibitors of Protein-tyrosine Phosphatase 1B

Residues Distant from the Active Site Influence Protein-tyrosine Phosphatase 1B Inhibitor Binding

Study on the Interactions of Two Isomer Selaginellins as Novel Small Molecule Inhibitors Targeting PTP1B by Docking and Molecular Dynamics Simulations

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