# A computational study to identify Sesamol derivatives as NRF2 activator for protection against drug-induced liver injury (DILI)

## TL;DR

This study identifies potential Sesamol derivatives that could activate the NRF2 pathway to protect against liver damage caused by drugs or their metabolites.

## Contribution

The study computationally identifies five Sesamol derivatives with potential NRF2 activation and good ADMET profiles for liver protection.

## Key findings

- Five Sesamol derivatives (66867225, 46148111, 12444939, 123892179, and 94817569) showed strong interactions with KEAP1-NRF2 and good stability in molecular dynamics simulations.
- Selected compounds exhibited favorable ADMET profiles and binding free energy, suggesting potential as NRF2 activators.
- The compounds demonstrated good protein-ligand complex stability and bond retention during simulations.

## Abstract

Drug-induced liver injury can be caused by any drugs, their metabolites, or natural products due to the inefficient functioning of drug-metabolizing enzymes, resulting in reactive oxygen species generation and leading to oxidative stress-induced cell death. For protection against oxidative stress, our cell has various defense mechanisms. One of the mechanisms is NRF2 pathway, when activated, protects the cell against oxidative stress. Natural antioxidants such as Sesamol have reported pharmacological activity (hepatoprotective & cardioprotective) and signaling pathways (NRF2 & CREM) altering potential. A Computational analysis was done using molecular docking, IFD, ADMET, MM-GBSA, and Molecular dynamic simulation of the Schrödinger suite. A total of 63,345 Sesamol derivatives were downloaded for the PubChem database. The protein structure of KEAP1-NRF2 (PDB: 4L7D) was downloaded from the RCSB protein database. The molecular docking technique was used to screen compounds that can form an interaction similar to the co-crystalized ligand (1VX). Based on MM-GBSA, docking score, and interactions, ten compounds were selected for ADMET profiling and IFD. After IFD, five compounds (66867225, 46148111, 12444939, 123892179, & 94817569) were selected for molecular dynamics simulation (MDS). Protein–ligand complex stability was assessed during MDS. The selected compounds (66867225, 46148111, 12444939, 123892179, & 94817569) complex with KEAP1 protein shows good stability and bond retentions. In our study, we observed that the selected compounds show good interaction, PCA, Rg, binding free energy, and ADMET profile. We can conclude that the selected compounds can act as NRF2 activators, which should be validated using proper in-vivo/in-vitro models.