Abstract
Ferroptosis is a novel iron-dependent form of regulated necrotic cell death characterized by extensive lipid peroxidation arising from an impaired antioxidant capacity of the cell. It has been implicated in various pathophysiological conditions such as cancer and neurodegenerative diseases. Heme-oxygenase 1 (HO-1) contributes to ferroptosis through its breakdown of heme, releasing Fe2+, which could challenge the body’s ferritin systems during periods of heightened cellular stress, making HO-1 a promising target to exploit the therapeutic potential of ferroptosis. This study investigated a library of 136 marine-derived bioactive compounds for their interaction with HO-1 using in silico approaches. Based on a co-crystal structure, the compounds were docked on the target protein to assess binding free energies (BFE) and conformations. Clustering analysis yielded BFEs that ranged from 15.9 kcal/mol to –11.8 kcal/mol. Interaction analysis of the top 10 compounds with the most negative BFEs showed comparable interactions with the previously co-crystallized HO-1 inhibitor. Furthermore, the top compounds were subjected to ADMET analysis, and – although all exhibited drug-likeness – Lipinski violations,and toxicity risks were nonetheless predicted. The docking results of the top compound, paraminabeolide F (1), were then validated using molecular dynamics (MD) simulations over 100 ns through RMSD, RMSF, radius of gyration, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) analyses, which confirmed the favorable interactions with HO-1.
Published Version
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