Artificial neural network-based drug design for diabetes mellitus using flavonoids

• Published in: Journal of computational chemistry 2011-03, Vol.32 (4), p.555-567
• Main Authors: Patra, Jagdish C, Chua, Boon H
• Format: Article
• Language: English
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - metabolism; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; artificial neural networks; Diabetes; diabetes mellitus; Diabetes Mellitus - drug therapy; Drug Design; Enzymes; Experiments; Flavones - chemistry; Flavones - pharmacology; flavonoids; Flavonoids - chemistry; Flavonoids - pharmacology; Flavonols - chemistry; Flavonols - pharmacology; Humans; Metabolic disorders; Metabolites; Neural networks; Neural Networks (Computer); Oxidative stress; QSAR; Quantitative Structure-Activity Relationship; Studies
• ISSN: 0192-8651; 1096-987X
• DOI: 10.1002/jcc.21641

Diabetes mellitus is a chronic metabolic disease involving the failure to regulate glucose blood levels in the body and has been linked with numerous detrimental complications. Studies have shown that these complications can be linked to the activities of aldose reductase (AR), an enzyme of the polyol pathway. Flavonoids have been identified as good AR inhibitors (ARIs) and are also strong antioxidants with radical scavenging (RS) activity. As such, flavonoids show potential to become a better class of ARIs because they are able to concurrently address the oxidative stress issue. In this article, we carried out quantitative structure-activity relationship analysis of flavones and flavonols (members of flavonoid family) using artificial neural networks. Three computer experiments were conducted to study the influence of hydrogen (H), hydroxyl (OH), and methoxyl (CH₃) functional groups on eight substitution sites of the lead flavone molecule and to predict potential ARIs. Of 6561 possible flavones and flavonols, in experiment 1, we predicted 69 potent ARIs, and in experiment 2, we predicted 346 compounds with strong RS activity. In experiment 3, we combined these results to find overlapping compounds with both strong AR inhibition and RS activity and we are able to predict 10 potent compounds with strong AR inhibition (IC₅₀ < 0.3 μM) and RS activity (IC₂₅ < 1.0 μM). These 10 compounds show promise of being good therapeutic agents in the prevention of diabetic complications and is suggested to undergo further wet bench experimentation to prove their potency.