Computational Screening of Microbial Metabolites as Erythropoietin (EPO) Mimetics for the Treatment of Anemia.

Abstract

Anemia remains a critical global health burden, often driven by impaired erythropoietin (EPO) signaling, which reduces red blood cell production. While recombinant EPO therapy is effective, its high cost and associated safety concerns limit its accessibility. This study explores microbial metabolites as affordable and safe alternatives that act as EPO mimetics that can bind and activate the erythropoietin receptor (EPOR). A computational screening of 90 microbial bioactive compounds was conducted, and from those, 16 were selected for detailed analysis. The extracellular domain of EPOR (PDB: 1EBP) was used as the target protein. Molecular docking was performed using AutoDock, followed by ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling with SwissADME and ProTox-III. Protein-protein interaction (PPI) networks were also analyzed in Cytoscape, and the stability of the top complexes was validated via 100 ns molecular dynamics (MD) simulations. Docking results identified Abyssomicin W, Abyssomicin C, and Camptothecin as the top candidates with strong binding affinities (-7.60 kcal/mol) to EPOR. ADMET predictions confirmed their favorable drug-likeness and safety profiles, with Abyssomicin W exhibiting the most promising characteristics, including high gastrointestinal absorption, and no predicted hepatotoxicity or carcinogenicity. PPI network analysis underscored the functional relevance of EPOR in erythropoietic pathways, while molecular dynamics (MD) simulations revealed that Abyssomicin W and Camptothecin formed highly stable complexes with the receptor, whereas the Abyssomicin C complex was unstable. The integrated computational pipeline successfully identified Abyssomicin W as the most stable and promising EPO mimetic candidate. In conclusion, this study identifies Abyssomicin W as a potential and stable EPO mimetic candidate, highlighting the potential of microbial metabolites as cost-effective therapeutics for anemia. Further experimental validation, including direct binding and functional cell-based assays is recommended to confirm its efficacy and safety in biological systems.