Marine algal TNF-α inhibitors explored by comparative docking and molecular dynamics simulations.

Marine ecosystems are rich in bioactive metabolites that represent a promising source of inhibitors targeting inflammatory signaling pathways. Among these, tumor necrosis factor-alpha (TNF-α) is a central pro-inflammatory cytokine driving chronic inflammation and contributing to diseases such as inflammatory bowel disease and rheumatoid arthritis. In the current study, we aim to explore potential bioactive compounds derived from marine algae-a valuable source of novel chemical entities-using integrated computational approaches, including molecular docking and molecular dynamics simulations, to identify promising inhibitors of TNF-α. More than 2000 molecules from marine algae, found in the Comprehensive Marine Natural Products Database (CMNPD) and the Natural Product Activity and Species Source (NPASS) database, were filtered based on high reactivity (score of 4 or higher) and molecular weight between 200-500 g/mol. According to our pharmacophore-based molecular docking, a shortlist of critical TNF-α residues-including Glu116, Pro117, and Tyr119-was selected as drug-target sites for the proposed inhibitors, with Tyr119 as a major target residue. Further analysis using molecular dynamics (MD) simulation indicated that bioactive marine-algae-molecules can specifically and effectively target these active residues of TNF-α. Of these compounds, CHEMBL510230 from brown algae and Floridoside from red algae showed promising inhibitory potential by interacting with these residues. Estimating binding free energies using molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) analysis confirmed that while Floridoside exhibits a stronger average binding affinity, CHEMBL510230 engages a broader network of stable residue interactions, supporting the suitability of both candidates for further preclinical investigation.