AbstractBackgroundAutophagy dysfunction may lead to amyloid‐β (Aβ) secretion and directly influence the accumulation of intracellular Aβ and generation of extracellular Aβ plaque. Natural polyamine, spermidine present in all living organisms, is critically involved in cellular homeostasis maintenance and influences many biological processes, namely cell growth and proliferation, DNA and RNA stabilization, tissue regeneration, regulation of translation, and enzymatic modulation. Brain spermidine/polyamine levels decrease during aging and various neurodegenerative disorders leading to impairment in autophagy. Spermine synthase is an enzyme involved in biosynthesis of polyamines. It catalyzes the formation of spermine from spermidine. Thus, we focused to repurpose USFDA approved drugs to inhibit spermine synthase which may increase the spermidine levels in the brain.MethodSchrodinger Suite's Maestro graphical user interface was used to carry out computational simulation experiments. Spermidine structure and US‐FDA licensed molecules compounds were downloaded. The molecules were configured using LigPrep tool in maestro software of Schrodinger. Spermine synthase structure (3C6K) bound to 5‐methylthioadenosine (MTA) was downloaded from Protein Data Bank (PDB). After the protein was minimized, the 2D interaction of the ligand‐protein interaction was conducted to observe the amino acid interactions. Spermidine and USFDA licensed molecules were docked using the Schrodinger Glide module. In the present study, the MMGBSA tool is utilized to calculate the prediction of the top compounds. The MD simulation was performed on Schrodinger's Desmond module.ResultFor increasing spermidine pool in the brain by inhibiting spermine synthase, Ribavirin, Sapropterin and Theobromine were found to cross the BBB and have good inhibitory interactions with the enzyme in an in‐silico system. RMSD values for all these three drugs were not satisfactory, but other parameters like protein‐ligand contact‐interaction fraction, 2D interaction diagram and protein‐Ligand contacts through different amino acids present in 3C6K showed satisfactory results.ConclusionOur study showed that ribavirin, sapropterin and theobromine were able to show inhibitory interactions with the spermine synthase. Further, in vitro and in vivo studies may be done to search for the ability of these molecules in the treatment of cognitive dysfunction.