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.

Keywords: Density functional theory; Keap1; Molecular docking; Molecular dynamics.

Figure 1

Structure of Kelch-like ECH associated Protein-1 (KEAP-1).

Figure 2

The validation of docking performance by AutoDock Vina. The co-crystalized and docked (inhibitor K67) ligands are shown as sticks in blue and orange color, respectively.

Figure 3

Molecular interactions of 18-Alpha Glycyrrhetinic Acid, Maslinic Acid, and Resveratrol as shown in (A), (B), (C).

Figure 4

Represents the RMSD values of the protein-ligands complexes to the protein backbone for 20ns. RMSD of 4ZY3, 4ZY3-18-AGA, 4ZY3-MASA and 4ZY3-RES are shown in black, red, green and blue respectively.

Figure 5

Graphical representation of RMSF value of the complex.

Figure 6

Represents the ROG values of the protein-ligand complexes to the protein backbone for 20ns. ROG of KEAP1, KEAP1-MASA, KEAP1-18-AGA and KEAP1-RES are shown in black, red, and green respectively.

Figure 7

Represents the number of hydrogen bonds responsible for the stability of the complexes (Keap1-MASA, Keap1-18-AGA and Keap1-RES) throughout the 20ns.

Figure 8

Shows the highest occupied molecular orbital (HOMO), the lowest occupied molecular orbital (LUMO) and the molecular electrostatic potential (MEP) respectively for each of the compounds.