Exploring the inhibitory potentials of Momordica charantia bioactive compounds against Keap1-Kelch protein using computational approaches

Abstract

The search for Keap1 inhibitors as potential Nrf2 activator is a way of increasing the antioxidant status of the human cellular environ. In this research, we used in silico methods to investigate Keap1-kelch inhibitory potential of Momordica charantia's bioactive compounds in order to predict their Nrf2 activating potential. ADMET profiling, physicochemical properties, molecular docking, molecular dynamics, and Molecular Mechanics-Poisson Boltzmann Surface Area (g_MMPBSA) free energy calculation studies were executed to drive home our aim. Out of all the bioactive compounds of Momordica charantia, catechin (CAT) and chlorogenic acid (CGA) were selected based on their ADMET profile, physicochemical properties, and molecular docking analysis. Molecular docking studies of CAT and CGA to Keap1 kelch domain showed that they have - 9.2 kJ/mol and - 9.1 kJ/mol binding energies respectively with CAT having four hydrogen bond interactions with Keap1 while CGA had three. Analysis after the 30 ns molecular dynamics simulation revealed that CAT and CGA were both stable, although with minimal conformational alterations at the kelch pocket of Keap1. Finally, MMPBSA calculation of the Gibbs free energy of each amino acid interaction with CAT and CGA revealed that CAT had a higher total binding energy than CGA. Therefore, the Keap1 inhibitory capacities and the molecular dynamic characters of CAT and CGA at the Kelch domain of Keap1 suggest a putative Nrf2 signaling activating prowess.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-021-00100-2.

Keywords: Keap1; Molecular Mechanics-Poisson Boltzman Surface Area (g_MMPBSA); Molecular dynamics; Momordica charantia.

Fig. 1

Structure of the kelch domain of Kelch-like ECH Associated Protein-1 (KEAP-1)

Fig. 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

Fig. 3

The structure of Catechin (Left); Chlorogenic acid (Right)

Fig. 4

Binding Pockets and molecular interactions of CAT and CGA with 4ZY3 respectively

Fig. 5

Represents the RMSD values of the protein–ligand complexes to the protein backbone for 30 ns. RMSD of KEAP1, KEAP1-CAT and KEAP1-CGA are shown in black, red, and green respectively

Fig. 6

Represents the RMSF values of the protein–ligand complexes to the protein backbone for 30 ns. RMSF of KEAP1, KEAP1-CAT, and KEAP1-CGA are shown in black, red, and green respectively

Fig. 7

The contribution energies of Keap1 residues involved in Keap1-CAT and Keap1-CGA complexes

Fig. 8

Represents the ROG values of the protein–ligand complexes to the protein backbone for 30 ns. ROG of KEAP1, KEAP1-CAT and KEAP1-CGA are shown in black, red, and green respectively

Fig. 9

Depicts the intermolecular hydrogen bonds formed between KEAP1-CAT and KEAP1-CGA