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Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications.

ABSTRACT: Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure-activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of 'drug-likeness". Novel promising structures of putative multifunctional ARIs/AOs are designed.

SUBMITTER: Kovacikova L

PROVIDER: S-EPMC8151378 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications.

Kovacikova Lucia L Prnova Marta Soltesova MS Majekova Magdalena M Bohac Andrej A Karasu Cimen C Stefek Milan M

Molecules (Basel, Switzerland) 20210512 10

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a ...[more]

PMID: 34066081

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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

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications.

Publications

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications.

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