Unveiling S ‐Adenosylmethionine Decarboxylase Natural Antagonist to Block Polyamine Biosynthesis: An In Silico Investigation for Anticancer Drug

Polyamines (PAs) are crucial for the growth and division of mammalian cells and play a key role in biological processes that govern cellular proliferation, differentiation, programmed cell death, and tumorigenesis. Their increased levels are associated with cancer cell progression, and therefore, restricting their metabolism may impede cancer development. S ‐Adenosylmethionine decarboxylase (AdoMetDC) is the major protein that converts S ‐adenosylmethionine to decarboxy‐ S ‐adenosylmethionine, which is crucial for polyamines (spermidine and spermine) generation. Therefore, AdoMetDC inhibition is a viable therapeutic approach to suppress cancer by restricting polyamine biosynthesis. This study reports systematic cheminformatic drug discovery analyses to screen 98,247 natural compounds against AdoMetDC for a potential anticancer lead molecule. Molecular docking analysis reveals compound‐ZINC8876937 has a strong binding affinity (binding energy = −8.32 kcal/mol) compared to control‐M8M (binding energy = −6.08 kcal/mol). The predicted cytotoxicity for ZINC8876937 is class IV (LD 50 = 511 mg/kg), indicating promising safety characteristics. Further, molecular dynamics simulations indicated strong stability of ZINC8876937, and free energy analysis exhibited a greater binding free energy for ZINC8876937 (−15.03 kcal/mol) than control‐M8M (−10.47 kcal/mol). Further, a 1‐µs simulation‐based competitive inhibition analysis between ZINC8876937 and control‐M8M reveals that ZINC8876937 forms more stable interactions at the protein's binding pocket compared to control. These findings established compound‐ZINC8876937 as a promising natural anticancer drug candidate by inhibiting polyamine biosynthesis.