# Metabolite‐Based Network Pharmacology, Molecular Docking, and Dynamics Simulations to Preliminarily Verify Treating Diabetic Encephalopathy Effect of Kuwanon G

## TL;DR

This study explores how Kuwanon G, a compound from mulberry, may help treat diabetic encephalopathy by analyzing its metabolites and their effects on brain-related pathways.

## Contribution

The study introduces a novel integration of metabolite profiling, network pharmacology, and molecular simulations to explore Kuwanon G's therapeutic potential for diabetic encephalopathy.

## Key findings

- Kuwanon G's metabolites (N1, N4, N6, N8) showed strong binding to key targets like AKT1 and TNF, suggesting neuroprotective roles.
- Nine metabolites with high intestinal absorption and pharmacophore compatibility were identified as potential bioactive forms.
- Dynamics simulations confirmed stable interactions between metabolites and targets, highlighting their role in modulating neurodegeneration pathways.

## Abstract

Kuwanon G (KWG), a bioactive flavonoid from mulberry, exhibits potential neuroprotective effects against diabetic encephalopathy (DE), yet its metabolic fate and therapeutic mechanisms remain unclear. This study integrated ultra‐high‐performance liquid chromatography–quadrupole time‐of‐flight mass spectrometry (UHPLC‐Q‐TOF‐MS), network pharmacology, molecular docking, and dynamics simulations to characterize KWG's metabolic profile and evaluate its anti‐DE activity. In vivo and in vitro analyses identified 56 metabolites in rats, predominantly formed via oxidation, dehydrogenation, methylation, and glucuronidation. Nine metabolites with high intestinal absorption and pharmacophore compatibility were selected using Swiss ADME. Network pharmacology revealed core targets (AKT1, TNF, SRC, EGFR, ESR1) linked to DE, while molecular docking demonstrated strong binding affinities (−4.87 to −43.41 kcal/mol) between active metabolites (N1, N4, N6, N8) and these targets. Dynamics simulations confirmed stable interactions, highlighting metabolites' roles in modulating PI3K‐Akt signaling and neurodegeneration pathways. Notably, KWG itself exhibited negligible binding, suggesting its metabolites are the primary bioactive forms. These findings underscore the importance of gut microbiota‐mediated biotransformation in enhancing KWG's bioavailability and neuroprotective efficacy. This work provides critical insights into the metabolic activation of natural products and advances their application in functional foods or therapeutics for diabetes‐related complications.

This study investigates the neuroprotective effects of Kuwanon G (KWG) against diabetic encephalopathy (DE) by characterizing its metabolic profile and therapeutic mechanisms. Using UHPLC‐Q‐TOF‐MS, network pharmacology, molecular docking, and dynamics simulations, 56 metabolites were identified, with nine showing high intestinal absorption and pharmacophore compatibility. Key findings suggest that KWG's metabolites, particularly N1, N4, N6, and N8, modulate PI3K‐Akt signaling and neurodegeneration pathways, indicating their potential as therapeutic agents for DE.