Pharmacoinformatics-based prediction of potential Keap1 inhibitors from Hemidesmus indicus (L) R.Br. against oxidative stress-induced diseases

Abstract

The Keap1-Nrf2 pathway plays a prominent role in activating cytoprotective genes, detoxification and antioxidative defense enzymes against oxidative stress and xenobiotics-induced damage. Oxidative stress is involved in the initiation and progression of numerous health complications. The present study investigated the antioxidant potential of aqueous methanolic extract of Hemidesmus indicus (L) R.Br., followed by a pharmacoinformatics-based screening of novel Keap1 protein inhibitors. Initially, the antioxidant potential of this target plant was assessed by antioxidant assays (DPPH, ABTS radical scavenging and FRAP). H. indicus (L) R.Br. extract (100 µg mL− 1) showed 85 ± 2.917%, 78.783 ± 0.24% of DPPH, ABTS radicals scavenging activity, and 161 ± 4 µg mol (Fe (II)) g− 1 ferric ion reducing power. Further, a total of sixty-nine phytocompounds were derived from this plant through the IMPPAT database, and their three-dimensional structures were obtained from the PubChem database. The chosen sixty-nine phytocompounds were docked against the Kelch-Neh2 complex protein (PDB entry ID: 2flu, resolution 1.50 Å) along with the standard drug (CPU192018). The top scored three hits were selected, namely Hemidescine (− 11.30 Kcal mol− 1), Beta-Amyrin (− 10.00 Kcal mol− 1), and Quercetin (− 9.80 Kcal mol− 1) based on their binding affinities. The selected three hits showed significant drug-likeness properties with the least toxicity profile. Molecular dynamics simulation studies showed that all the protein-ligand complexes (Keap1-HEM, Keap1-BET and Keap1-QUE) were highly stable during the entire simulation period, compared to standard CPUY192018-Keap1complex. Based on these findings, the top-scored three phytocompounds may be used as a significant and safe Keap1 inhibitor and could potentially use for oxidative stress-induced health complications.