Abstract
This work utilizes the anthraquinone (AQ) database to identify potential inhibitors of the RIPK1 protein for developing medicines targeting AP-associated necroptosis. Screening for necroptosis-related genes that play a crucial role in AP is based on the GEO and GSEA databases. An optimum AQ for receptor-interacting protein kinase 1 (RIPK1) inhibition was virtually screened using the Discovery Studio 2019 tool, with a previously described RIPK1 inhibitor (necrostatin-1) as a reference ligand. Using LibDock and CDOCKER molecular docking, an AQ that robustly binds to RIPK1 was identified. The DOCKTHOR web server was used to calculate the ligand−receptor binding energy. The pharmacological properties and toxicity of potential AQ were evaluated using the ADME module and ProTox-II web server. The stability of ligand−receptor complexes was examined using molecular dynamics (MD) simulation. All 12 AQs showed solid binding activity to RIPK1, 5 of which were superior to necrostatin-1. Rheochrysin and Aloe-Emodin-8-O-Beta-D-Glucopyranoside (A8G) were safe RIPK1 inhibitors based on pharmacological characterization and toxicity studies. Additionally, the potential energy of the candidate AQs with RIPK1 was greater than that of the reference ligand, necrostatin-1. MD simulations also showed that the candidate AQs could bind stably to RIPK1 in the natural environment. Rheochrysin and A8G are safe and effective anthraquinones that inhibit the RIPK1 protein. This research takes a first step toward developing RIPK1 inhibitors by screening AQs that have the potential to be more effective than the reference ligand necrostatin-1.