# Bioactive small compounds effectively inhibit ChREBP overexpression to treat NAFLD and T2DM: A computational drug development approach

## TL;DR

This paper identifies five natural compounds that may inhibit ChREBP, a protein linked to non-alcoholic fatty liver disease and type-II diabetes, using computational drug design.

## Contribution

The study introduces five promising natural small molecules as potential inhibitors of ChREBP for treating NAFLD and T2DM.

## Key findings

- Five compounds (dieckol, isocorilagin, stachyurin, stachysetin, and thonningianin A) showed strong binding affinity to ChREBP.
- MD simulations confirmed the stability of the protein–ligand complexes of these compounds.
- ADMET analysis indicated the compounds are safe and effective drug candidates.

## Abstract

A glucose-dependent carbohydrate-signaling gene regulator named Carbohydrate response element binding protein (ChREBP), has recently been discovered as a major metabolic regulator of enzymes involved in the progression of non-alcoholic fatty liver disease (NAFLD) and type-II diabetes mellitus (T2DM). As a result, this research is aimed to identify natural small molecules as drug candidates that target the ChREBP in order to counter aggressive NAFLD and T2DM. A comprehensive in silico drug design strategy was implemented to find possible inhibitors of the targeted protein. A site-specific molecular docking approach was used to screen 20 FDA approved anti-diabetic drugs and 494 phytochemicals from the natural sources against the ChREBP, and the top ten compounds were selected for further studies based on their binding affinities. The ADME and toxicity profiles of the selected ten drug compounds demonstrated their efficacy and safety. The result of the MD simulations of the protein–ligand complex structures indicated their stability and potential activity. A comprehensive data screening process following docking, ADMET properties, and MD simulation approaches, five compounds (dieckol, isocorilagin, stachyurin, stachysetin and thonningianin A) with favorable values against the targeted ChREBP were demonstrated which indicates their strong potential as promising and effective drug candidates for the treatment of NAFLD and T2DM.

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