AbstractBackgroundIn Alzheimer’s disease (AD), Aβ directly downregulates the activity of the Akt pathway by decreasing insulin receptor, IGF, IGFR and PI3K levels leading to reduced phosphorylation of Akt. The diminished inhibitory influence of Akt results in the deranged activity of GSK‐3β, Forkhead, BAD, mTOR pathways, which leads to increased tau phosphorylation, oxidative stress, and cell death. Many researchers have proven that activating the Akt pathway can ameliorate cognitive defects like learning and memory in AD and protect neurons from cell death.MethodMaestro platform from Schrodinger Inc. was used for shape‐based screening by using already know activators like SC79, inositol‐(1,3,4,5)‐tetrakisphosphate, Baicalin, Puerarin, and Chlorogenic acid as a template to screen Asinex and enamine CNS databases. Later, pharmacophore models like receptor‐ligand complex (1UNQ PBD) pharmacophore, Receptor cavity‐based pharmacophore, and multiple ligand‐based pharmacophores were built and used to screen the same databases. Lastly, the Fingerprint‐based 2D QSAR model was built using known active ligands and inactive ligands. Seventeen QSAR models which predicted the activity without error were used to screen databases. Ligands that came out positive in a maximum number of all models were selected and then docked with PH domain of the Akt1, which is the only PDB(1UNQ) with PH domain in an active conformation.ResultDue to the lack of crystal structure of Akt1 protein in active conformation, ligand‐based approach was used. After all the approaches mentioned in the methodology, we selected Asinex CNS ‐275 and Enamine CNS‐76 lead molecules and docked them with PH domain of Akt1. After docking, each molecule pose was analyzed and molecules that interact with the critical residues like Arg 23, Arg 25, Lys 14, Arg 86, Asn 53 essential for activation were selected. Using all these approaches from the library of 2,00,000 compounds, we have narrowed it down to 13 lead molecules.ConclusionUsing an in silico‐based approach, we identified lead molecules that may act as Akt activators and help alleviate the harmful effect of tau hyperphosphorylation. However, an in vivo experiment is needed for supporting this claim.