Natural product inhibitors as potential drug candidates against Alzheimer?s disease: Structural-based drug design, molecular docking, molecular dynamic simulation experiments, and ADMET predictions

Alzheimer's disease (AD) is currently an incurable ailment with complicated-mechanism that causes intellectual impairment in adults mostly from 65 years old and above. Hence, immediate effort and actions are required to prevent or cure this life-threatening disease. There are currently four medications in the market, all of which have minimal therapeutic potential and are quite hazardous. The familiar pharmacological targets and inter-vention principles were assessed using an in-silico technique. This strategy emphasizes the benefits of natural products operating in a polytherapeutic manner over a monotherapy approach to AD treatment. A protein target with ID code 4EY7 was utilized in this research and it was chosen based on established literature studies and reasons such as lower resolution value (2.3 angstrom), no mutation, Homo Sapiens, and X-ray diffraction method, the protein target interacted with some natural products, with greater interactions, higher binding scores, and improved enhanced drug-like properties and drug kinetic parameters The findings of these studies can be used to design promising pharmacotherapeutic compounds for the treatment of AD Natural products were docked with protein targets, resulting in a molecule with the maximum binding energy of-19.82 kcalmol-1. It was utilized as a template for designing natural product derivatives with lower binding energies, high stability, and improved interactions. Compound Y5 has a docking score of-26.29 kcalmol-1. The molecular dynamics (MD) Simulation used docked protein complexes with selected ligands as standard (refer-ence) further verified the docking results. RSMD showed that compound Y5 remain within the inhibitor binding site all through the simulation period and reached equilibrium more rapidly compared to the standard. Also, the RMSF, Rg curve, and SASA gives brilliant results which further confirmed the stability of compound Y5. Lastly, the ligand hydrogen bond was examined, compound Y5 formed more hydrogen bonds with protein during the 100ns simulation indicating that the compound Y5 complex was more stable relative to the harmine. The compounds' drug-likeness and pharmacokinetics features were also evaluated, and all showed positive results. Alzheimer's as a consequence, these designed compounds with variety of inherent endowment of therapeutic ability and support in successful research and development, leading to excellent therapeutic effects, low toxicity, and brilliant kinetic abilities, making substantial contributions to the treatment of AD.