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

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. Graphical abstract

Potential Role of Dietary Phenolic Compounds in the Prevention and Treatment of Rheumatoid Arthritis: Current Reports

“…In addition, docking studies revealed that the most predominant compounds in this tea, which were, caffeine, catechin, catechin gallate, epicatechin, epigallocatechin, epigallocatechin gallate, epicatechin gallate, gallic acid, and gallocatechin, revealed strong Focusing on their potential to interact with the Nrf-2 pathway, Diniyah and colleagues [200] revealed that catechin, epicatechin, and gallic acid from non-oilseed legumes present high binding affinities with Keap1, a protein that activates the degradation of Nrf-2, and are therefore promising new Nrf2 activators. Similar results were found involving hesperetin, hesperidin, naringenin, naringin, narirutin, neohesperidin, neohesperidin dihydrochalcone, and nobiletin citrus-derived flavonoids [201] and sesamol isolated from Sesamum indicum L. seed oil [183]. Mice treated with 37.5, 75, and 150 mg/kg green tea every 8 h by intragastric administration, which were then sacrificed 4, 12, and 20 h after administration, showed higher levels of antioxidative enzymes and liver phase II enzymes.…”

“…This is the major pathway involved in the maintenance of homeostatic responses by raising intracellular defense mechanisms and regulating the heme oxygenase-1 axis, controlling macrophage activation and the NF-κB pathway, and reducing stress oxidative and inflammation [181]. Under quiescent conditions, Kelch-like ECH-associated protein 1 (Keap 1) holds Nrf2 in the cytoplasm, promoting its ubiquitination and subsequent proteolysis; however, under pathology conditions, Nrf2 is released from Keap1 and enters the nucleus, where the transcription of antioxidant enzymes occurs [182][183][184].…”

“…Among the most promising therapeutic and adjuvant approaches, polyphenols assume a prominent interest since they have already been shown to possess notable capabilities to restore oxidative stress and inflammation near basal levels by interacting with Keap1 protein, avoiding its linkage with its binding site in Nrf-2. This subsequently, causes the dissociation of Keap1 from Nrf2, leading to the transcriptional activation of Nrf-2 and, hence, stimulating intracellular antioxidant enzyme (glutathione, catalase, and superoxide dismutase) activity, and, of course, neutralizing oxidative stress [182][183][184].…”

Cytotoxicity effect, network pharmacology, molecular docking, and molecular dynamics simulation of new mono-chalcone compounds for breast cancer

“…The mean values of Rg and SASA were conducted across the simulated trajectories, as presented in Table 5. A slight increase in Rg values observed in protein-ligand conformation compared to reference proteins was noticeable indicating that there was a reduction in their structural compactness, hence hinting that these proteins undergo expansion upon binding with ligands [69]. In contrast, the Rg values of the ligated proteins that were not affected by the ligand were found to be similar to those of the proteins that were not bound to any ligand.…”

“…According to Mili et al [69], there is a potential for the compounds attached to the protein receptors to exhibit a slightly reduced level of compactness compared to the reference proteins in their unligated state. The SASA value quantifies the extent of the molecular surface that is in contact with the hydrophobic (solvent) environment [70].…”