Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3β, NMDA-Receptor, and BACE-1 for the Management of Alzheimer's Disease

The complexity of Alzheimer's disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3β, NMDA receptor, and BACE-1 and thereafter validated the best hit through molecular dynamics simulation (MDS). The results demonstrated that out of 2029 compounds, only 51 compounds exhibited better binding interactions than native ligands, with all three protein targets (NMDA, GSK3β, and BACE) considered multitarget inhibitors. Among them, F1094-0201 is the most potent inhibitor against multiple targets with binding energy -11.7, -10.6, and -12 kcal/mol, respectively. ADME-T analysis results showed that F1094-0201 was found to be suitable for CNS drug-likeness in addition to their other drug-likeness properties. The MDS results of RMSD, RMSF, Rg, SASA, SSE and residue interactions indicated the formation of a strong and stable association in the complex of ligands (F1094-0201) and proteins. These findings confirm the F1094-0201's ability to remain inside target proteins' binding pockets while forming a stable complex of protein-ligand. The free energies (MM/GBSA) of BACE-F1094-0201, GSK3β-F1094-0201, and NMDA-F1094-0201 complex formation were -73.78 ± 4.31 kcal mol^-1, -72.77 ± 3.43 kcal mol^-1, and -52.51 ± 2.85 kcal mol^-1, respectively. Amongst the target proteins, F1094-0201 have a more stable association with BACE, followed by NMDA and GSK3β. These attributes of F1094-0201 indicate it as a possible option for the management of pathophysiological pathways associated with AD.