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Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes.

ABSTRACT: An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands.

SUBMITTER: Genovese M

PROVIDER: S-EPMC8540617 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes.

Genovese Massimo M Imperatore Concetta C Casertano Marcello M Aiello Anna A Balestri Francesco F Piazza Lucia L Menna Marialuisa M Del Corso Antonella A Paoli Paolo P

Marine drugs 20210924 10

An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleg ...[more]

PMID: 34677434

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Project description:BackgroundDiabetes remains a leading cause of morbidity and mortality due to various complications induced by hyperglycemia. Inhibiting Aldose Reductase (AR), an enzyme that converts glucose to sorbitol, has been studied to prevent long-term diabetic consequences. Unfortunately, drugs targeting AR have demonstrated toxicity, adverse reactions, and a lack of specificity. This study aims to explore African indigenous compounds with high specificity as potential AR inhibitors for pharmacological intervention.MethodologyA total of 7,344 compounds from the AfroDB, EANPDB, and NANPDB databases were obtained and pre-filtered using the Lipinski rule of five to generate a compound library for virtual screening against the Aldose Reductase. The top 20 compounds with the highest binding affinity were selected. Subsequently, in silico analyses such as protein-ligand interaction, physicochemical and pharmacokinetic profiling (ADMET), and molecular dynamics simulation coupled with binding free energy calculations were performed to identify lead compounds with high binding affinity and low toxicity.ResultsFive natural compounds, namely, (+)-pipoxide, Zinc000095485961, Naamidine A, (-)-pipoxide, and 1,6-di-o-p-hydroxybenzoyl-beta-d-glucopyranoside, were identified as potential inhibitors of aldose reductase. Molecular docking results showed that these compounds exhibited binding energies ranging from -12.3 to -10.7 kcal/mol, which were better than the standard inhibitors (zopolrestat, epalrestat, IDD594, tolrestat, and sorbinil) used in this study. The ADMET and protein-ligand interaction results revealed that these compounds interacted with key inhibiting residues through hydrogen and hydrophobic interactions and demonstrated favorable pharmacological and low toxicity profiles. Prediction of biological activity highlighted Zinc000095485961 and 1,6-di-o-p-hydroxybenzoyl-beta-d-glucopyranoside as having significant inhibitory activity against aldose reductase. Molecular dynamics simulations and MM-PBSA analysis confirmed that the compounds bound to AR exhibited high stability and less conformational change to the AR-inhibitor complex.ConclusionThis study highlighted the potential inhibitory activity of 5 compounds that belong to the African region: (+)-Pipoxide, Zinc000095485961, Naamidine A, (-)-Pipoxide, and 1,6-di-o-p-hydroxybenzoyl-beta-d-glucopyranoside. These molecules inhibiting the aldose reductase, the key enzyme of the polyol pathway, can be developed as therapeutic agents to manage diabetic complications. However, we recommend in vitro and in vivo studies to confirm our findings.

Dataset Information

Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes.

Publications

Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes.

Similar Datasets

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