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

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.

Molecular docking and dynamics guided approach to identify potential anti-inflammatory molecules as NRF2 activator to protect against drug-induced liver injury (DILI): a computational study.

Inflammation and oxidative stress can contribute to the etiology of metabolic and chronic illnesses. The ability to prevent oxidative stress induced diseases such as cancer, cardiovascular disease, Alzheimer's disease, and others has been the subject of global research. Drug-induced liver injury (DILI) pathogenesis can be either due to oxidative stress or inflammatory response elicited by the drug, its metabolite, or herbal supplements. Our present research uses computational studies to identify a molecule with anti-inflammatory properties that can operate as an NRF2 activator. Acquiring and preparing the KEAP1-NRF2 Protein (PDB: 4L7D) with Schrodinger Suite was followed by developing a ligand library (Anti-inflammatory library downloaded from ChemDiv database). Molecular docking studies were performed in HTVS, SP, and XP modes, respectively. Based on the docking score, interaction, ADMET and binding free energy, the top ten compounds were selected and subjected to induced-fit docking (IFD) analysis for further study. The top three molecules were chosen for a molecular dynamics (MD) simulation study. Using the Desmond module of the Schrodinger Suite, the stability of the protein-ligand complex and protein-ligand contact throughout 100ns were evaluated during the MD simulation study. In our study, it was observed that three compounds exhibit exceptional stability and retain the essential interaction throughout the studies, and it is anticipated that these compounds may act as effective NRF2 activators. Further in vitro and in vivo assessments can be conducted to determine its potential to prevent DILI via acting as an NRF2 activator for future drug development.

A comprehensive review on Sesamum indicum L.: Botanical, ethnopharmacological, phytochemical, and pharmacological aspects.

ETHNOPHARMACOLOGICAL RELEVANCE: Sesamum indicum L. (Pedaliaceae) is an annual plant, which has been domesticated for well over 5000 years. It is widely cultivated for its seeds and is one of the oldest known oilseed crops. Traditionally, its seeds, seed oil, and different organs of the plant have been used to treat various diseases or conditions like ulcers, asthma, wound healing, amenorrhea, hemorrhoids, inflammations, etc. AIM OF THE REVIEW: The main aim of this review is to provide an outline and to assess the reported ethnopharmacological, phytochemical, pharmacological and toxicological studies of Sesamum indicum L. MATERIALS AND METHODS: An extensive literature survey was done on various search engines like PubMed, Web of Science, Scopus, SciFinder, Google Scholar, Science direct, etc. Other literature sources like Wikipedia, Ethnobotanical books, Chapters were also studied to get maximum information possible on the Sesamum indicum L. RESULTS: Over 160 different phytochemical compounds have been characterized and isolated from seeds, seed oil, and various plant organs, including lignans, polyphenols, phytosterols, phenols, anthraquinones, naphthoquinones, triterpenes, cerebroside, fatty acids, vitamins, proteins, essential amino acids, and sugars using suitable analytical techniques (e.g., LC-MS, GC-MS, HPTLC, HPLC). All the reported pharmacological activities like antioxidant, anticancer, antipyretic, antihypertensive, hepatoprotective, and anti-inflammatory are due to the virtue of these phytochemical compounds. CONCLUSION: This review mainly highlights the botanical aspect of Sesamum indicum and its phytochemical constituents, ethnomedicinal uses, different pharmacological activities followed by ongoing clinical trials and future prospects. Sesamum indicum has great importance in traditional Indian medicine, which is further supported by modern pharmacological studies, especially in hepatoprotection, inflammation, and cancer. Several researchers have suggested that Sesamum indicum extracts and isolated compounds could have a wide therapeutic potency range. More research is needed to uncover key features of Sesamum indicum in medical practice, such as structure-activity relationships, toxicity, and therapeutic potential. In order to fully explore the plant's potential, safety assessments and implementation of an integrated cultivation method are also areas that need to investigate.