Mini ReviewNovel protein tyrosine phosphatase 1B inhibitors: interaction requirements for improved intracellular efficacy in type 2 diabetes mellitus and obesity control
Highlights
► PTP1B, an active player in insulin and leptin resistance. ► PTP1B chemical structure, substrates, activation/inactivation. ► The structural features of PTP1B molecule relevant to the interactions with inhibitors. ► The progress towards inhibitors with enhanced membrane permeability, affinity, specificity, and potency on intracellular PTP1B.
Section snippets
PTP1B, an active player in insulin and leptin resistance
In physiologic condition, two hormones are crucial for long-term energy storage: insulin, that controls the pathways responsible for glucose uptake and lipogenesis, and leptin, that regulates food intake and peripheral energy expenditure. Resistance to insulin and leptin is the hallmark in common for type 2 diabetes mellitus and obesity, two pathologies continuously increasing in prevalence worldwide. Insulin resistance is manifest in adipocytes, skeletal muscle, and hepatocytes by defects of
PTP1B chemical structure, substrates, activation/inactivation
PTP1B (encoded by Ptpn1 gene) is a prototypical member of the PTP family of enzymes. It is a ubiquitously expressed enzyme (EC 3.1.3.48) known to dephosphorylate and control a multitude of signaling events during cell growth, differentiation, apoptosis, and cell movement.
PTP-1B is a 50 kDa monomeric enzyme containing 435 amino acids. The N-terminal domain (amino acids 1–298) includes the catalytic domain which contains two aryl phosphate-binding sites: a high-affinity catalytic site (containing
The structural features of PTP1B molecule relevant to the interactions with inhibitors
The most efficient inhibition is accomplished when the inhibitor occupies the high-affinity catalytic site of PTP1B. The latter is defined by residues 214–221 (the P-loop) and has preference for acidic residues. Therefore, inhibitors aimed to occupy the active site should be anionic charged at physiologic pH, and possess polar groups. The former most investigated PTP1B inhibitor which binds to the active site of the phosphatase enzyme is vanadate. Within the active site, vanadate forms a
Toward inhibitors with increased efficacy on intracellular PTP1B and of benefit in type 2 diabetes mellitus and obesity control
The ideal inhibitor should possess the ability to cross the cell membrane, to recognize distinctively cytoplasmic PTP1B, bind it with high affinity, and block the phosphatase reaction as well as the subsequent steps in the insulin or leptin signaling pathway. A strategy towards more membrane permeable PTP1B inhibitors is to enhance their hydrophobic character by the insertion of a lipophilic phenylimino moiety [30]. Another strategy consists in synthesis of ester derivatives of inhibitors which
Emerging approaches
As inhibition of PTP1B enzyme activity is of promise for alleviating insulin and leptin resistance, studies on PTP1B inhibitors are worthwhile. From the examination of the last 3 years data, several approaches appear as valuable in the near future: (i) identification of novel pro-drug delivery inhibitors, (ii) design of efficient drug-like PTP1B inhibitors, able to interact both with the catalytic as well as the secondary binding pockets of PTP1B molecule, (iii) discovery of inhibitors to be
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2022, Free Radical Biology and MedicineCitation Excerpt :Protein Tyrosine Phosphatase 1B Inhibitors (PTP1B Inhibitors): The PTP1B via dephosphorylating insulin receptor and insulin receptor substrate acts a s a negative regulator of insulin signaling. Moreover, it also suppresses leptin signaling via dephosphorylating the JNK2 resulting in leptin resistance [301,302]. Therefore, inhibition of PTP1B is a potential therapeutic approach for treating insulin resistance, hyperglycemia and obesity.
Recent updates on development of protein-tyrosine phosphatase 1B inhibitors for treatment of diabetes, obesity and related disorders
2022, Bioorganic ChemistryCitation Excerpt :Chemical modification of active site Cys215, leads to inactivation of PTP1B enzyme activity, either by oxidation or by S-nitrosylation. A global conformational change of PTP1B molecule occurs when the C-terminal domain influences the N-terminal domain which further allows formation of direct contacts between the catalytic domain and the phosphorylated substrates [397]. The catalytic domain of PTP1B possesses approximately 40% sequence identity with the other family members and in vitro it catalyzes the dephosphorylation of tyrosine phosphorylated peptides and proteins.
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2021, Journal of Molecular Graphics and ModellingCitation Excerpt :Different pharmacological properties of berberine including anticonvulsant [38], antidepressant [28,38], anti-Alzheimer [28], anti-arrhythmic [38], anti-inflammatory [38], antiviral [39], antibacterial [39], antineoplastic [35] and anti-diabetic [40,41] have been reported in both in vivo and in vitro studies. Berberine besides having anticancer properties, is an essential therapeutic phytochemical agent [28,33] with anti-diabetic, anti-malaria, anti-AIDS, anti-jaundice, anti-cholera, anti-diarrhea, anti-leprosy, and anti-inflammation effects [35,37,42–49]. For drug designing and discovery, the computational technique for screening natural inhibitors is gaining attention among researchers [50].