Ganoderic acid targeting nuclear factor erythroid 2-related factor 2 in lung cancer.

Lung cancer causes huge mortality worldwide, and targeting new pathway may provide an alternative in modulating signaling in cancer. Nuclear factor erythroid 2-related factor 2 is the major regulator of endogenous and exogenous stress by activating numerous antioxidant genes critical in cancer, Alzheimer's, Parkinson's, and inflammatory bowel diseases. Ganoderic acid is a triterpene from basiodiomycetes fungus Ganoderma lucidum with numerous therapeutic effects. In this study, ganoderic acid and its 50 isomers and natural activators were docked by receptor-based molecular docking using Maestro 9.6 (Schrödinger Inc.) in the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 signaling pathway. The receptor-based molecular docking reveals the best binding interaction of nuclear factor erythroid 2-related factor 2 and ganoderic acid A with GScore (-9.69) (kcal/mol), Lipophilic EvdW (-1.83), Electro (-0.72), Glide emodel (-73.369), H bond (-1.1), molecular mechanics/generalized Born surface area (-75.541) with Leu 718, Asp 800, Cys 797 residues involved in hydrogen bonding. The calculated docking energy highlights the lipophilic, hydrogen bonding, pi-pi stacking interactions, and non-covalent bonding. Analysis showed the involvement of cysteine and serine residues which were crucial in the activation and translocation from cytoplasm to the nucleus in the nuclear factor erythroid 2-related factor 2 signaling process. The molecular docking tool QikProp analyzed the absorption, distribution, metabolism, excretion, and toxicity but needs some modifications in their structure to satisfy Lipinski's rule. Ganoderic acid A is a best docked isoform which inhibits the cell proliferation, viability, migration, and reactive oxygen species and messenger RNA expression of nuclear factor erythroid 2-related factor 2 in H460 cells.