In the current paper, the donepezil piperidine ring core was substituted with various natural drug cores from available natural product cores from PubMed, and the ligand library was generated as shown in table 01. The generated library compound structures were optimized using the DFT methods (B3LYP-D3/6-31G** Basis set) and ligands are used for docking to 1EVE Protein-data-bank protein file, The protein was prepared using the Autodock and grid file was generated around the co-crystalize inhibitor ligand E2020. The piperidine core was substituted with different cores the generated compound structures optimized in gaussian 09 software using B3LYP-d3 / 6-31G** basis set were then docked using Autodock Vina embedded in PyRx software , The structures showing the optimal binding interaction and well binding score in the binding energy scoring function are further analyzed for the lead molecules and the data displayed in table 02. The best candidates are selected and the various R groups are substituted and the binding energy and scoring interaction are analyzed using the PyRx tool and Autodock vina and the post dock the results are analyzed using pymol and discovery studio discussed below and the best binding posses with zero rmsd in the upper and lower band which having highest binding energy are discussed in Target (macromolecule) Modelling and Docking.