In Silico Analysis of the Interaction of Marine-derived Bioactive Compounds with the NLRP3 Inflammasome NACHT Domain

Cell death plays a homeostatic role in the life of a multicellular organism such as in removing damaged, unwanted, or excess cells, and aiding the normal development of organisms. Pyroptosis is an immunomodulatory form of regulated cell death that is mediated by the pore-forming action of the gasdermin protein family, and has been linked to various diseases including cancer, neurodegeneration, and infection. Targeting pyroptosis therefore could have potential therapeutic benefit, for instance, via the inhibition of its execution. In this regard, marine-derived compounds can offer possible novel structures and scaffolds by which potential pyroptosis inhibitors can be designed. In this study 153 mareine-derived compounds were investigated for their in silico interaction with the NLRP3 inflammasome NACHT domain through molecular docking, ADMET profiling, and key interaction analysis. Docking of the compounds on the target protein based on a previously solved co-crystal structure yielded binding free energy (BFE) values between–10.8 to 82 kcal/mol. Interactions of the top-performing compounds with critical protein residues were predominantly non-covalent in nature and displayed a great degree of similarity to the co-crystalized inhibitor. The top performing compounds also displayed drug-likeness with varying levels of toxicity risks based on ADMET analysis, and (S)-6’-debromohamacanthin was determined to have the most potential having zero Lipinski violations and exhibiting no toxicity risks.