Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Abstract

Inhibitors of Keap1 would disrupt the covalent interaction between Keap1 and Nrf2 to unleash Nrf2 transcriptional machinery that orchestrates its cellular antioxidant, cytoprotective and detoxification processes thereby, protecting the cells against oxidative stress mediated diseases. In this in silico research, we investigated the Keap1 inhibiting potential of fifty (50) antioxidants using pharmacokinetic ADMET profiling, bioactivity assessment, physicochemical studies, molecular docking investigation, molecular dynamics and Quantum mechanical-based Density Functional Theory (DFT) studies using Keap1 as the apoprotein control. Out of these 50 antioxidants, Maslinic acid (MASA), 18-alpha-glycyrrhetinic acid (18-AGA) and resveratrol stand out by passing the RO5 (Lipinski rule of 5) for the physicochemical properties and ADMET studies. These three compounds also show high binding affinity of -10.6 kJ/mol, -10.4 kJ/mol and -7.8 kJ/mol at the kelch pocket of Keap1 respectively. Analysis of the 20ns trajectories using RMSD, RMSF, ROG and h-bond parameters revealed the stability of these compounds after comparing them with Keap1 apoprotein. Furthermore, the electron donating and accepting potentials of these compounds was used to investigate their reactivity using Density Functional Theory (HOMO and LUMO) and it was revealed that resveratrol had the highest stability based on its low energy gap. Our results predict that the three compounds are potential drug candidates with domiciled therapeutic functions against oxidative stress-mediated diseases. However, resveratrol stands out as the compound with the best stability and therefore, could be the best candidate with the best therapeutic efficacy.

Antioxidant mechanism of Rosmarinus officinalis essential oil ameliorating pulmonary oxidative stress by activating NRF2 signaling pathway

“…Inhibitors of Keap1 have the potential to interrupt the covalent interaction between Nrf2 and Keap1. This disruption unleashes the transcriptional machinery of Nrf2, which coordinate cellular antioxidant/detoxi cation processes, safeguard cells against oxidative stress-induced disorders [30]. Although the literature extensively demonstrates the antioxidant properties of REO, certain exclusively detected volatile compounds within the REO likely have signi cantly contributed to its notable antioxidant capacity identi ed in this study.…”

In vitro and in silico perspectives on the activation of antioxidant responsive element by citrus-derived flavonoids

“…Based on the DFT computation at the same level of theory, the MEP of chemicals could visually represent the electronic distribution ( 47 ). The calculated MEPs in Figure 4 show a surface analysis throughout the tested compounds calculated with the B3LYP density functional method.…”

Molecular Mechanics with Generalized Born Surface Area (MMGBSA) Calculations and Docking Studies Unravel some Antimalarial Compounds Using Heme O Synthase as Therapeutic Target

“…Specifically, Meliantrol and Tamarixetin exhibit substantially improved binding affinities with binding free energies of À 32.30 kJ/mol and À 24.91 kJ/mol, respectively, whereas Inabenfide has a comparatively lower binding free energy of À 21.38 kJ/mol. Furthermore, it is worth noting that Meliantrol and Tamarixetin also display better hydrogenbonding contributions (À 2.22 and À 2.98), in contrast to Inabenfide (À 0.14) and it has been reported by [39,53] that the more hydrogen bonds in the interaction profile of a Protein-Ligand complex, the more stable the protein-ligand complex will be as hydrogen bonds between ligands and proteins indicate a strong intermolecular interaction. It can be deduced from the result of molecular docking that Meliantrol has the best interaction profile of the 2 selected ligands, even better than Inabenfide, with a binding affinity of À 8.4 Kcal/mol (constituted by 3 hydrogen bonds and 2 other bonds as seen in Figure 2) as compared to Tamarixetin À 8.3 Kcal/mol (constituted by 3 hydrogens and 6 other bonds as presented in Figure 2) and Inabenfide À 8.1 Kcal/mol.…”