Integrated pharmacophore and docking-based designing of dual inhibitors of aldose reductase (ALR2) and protein tyrosine phosphatase 1B (PTP1B) as novel therapeutics for insulin-resistant diabetes and its complications

2014 ◽  
Vol 29 (2) ◽  
pp. 109-125 ◽  
Author(s):  
Bhawna Vyas ◽  
Om Silakari ◽  
Maninder Kaur ◽  
Baldev Singh
Keyword(s):  
Aldose Reductase ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Novel Therapeutics ◽  
Insulin Resistant ◽  
Dual Inhibitors

scholarly journals In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 330
Author(s):  
Rosaria Ottanà ◽  
Paolo Paoli ◽  
Mario Cappiello ◽  
Trung Ngoc Nguyen ◽  
Ilenia Adornato ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Aldose Reductase ◽  
Protein Tyrosine Phosphatase ◽  
Complex Disease ◽  
Tyrosine Phosphatase ◽  
C2c12 Cell ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
In Silico Docking ◽  
Multiple Ligands

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.

scholarly journals Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4818
Author(s):  
Massimo Genovese ◽  
Ilaria Nesi ◽  
Anna Caselli ◽  
Paolo Paoli
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Antidiabetic Drugs ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Lead Compounds ◽  
Limited Effectiveness ◽  
Biological Target ◽  
Dual Inhibitors

Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D.

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