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

Abstract

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.

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders

“…The software's default values were used for all other docking parameters. The following relationship was used to compute the binding affinity (Ki) of ligands for the target enzyme from the binding energy (∆G) [11,12]:…”

“…Using "Desmond (Schrodinger-2020, LLC, New York, NY, USA)", the best-scoring ligand's MD simulation was carried out in complex with each of its targeted enzymes (GSK-3β, NMDA, and BACE-1), in triplicate as previously mentioned [12,44]. After molecular docking, the best-hit protein-ligand complexes were loaded into Schrodinger software's Maestro interface.…”

“…There are only two classes of FDA-approved medication available that are used for the management of AD, both of which are protein (enzyme or receptor) inhibitors [9]. However, there are various enzymes and receptors involved in the pathogenesis and progression of AD, including BACE-1, GSK-3β, CDK5, AChE, BuChE, MAO-A, MOA-B, NMDA, and ROCK2, that can be targeted therapeutically-either individually or collectively [10][11][12][13][14][15].…”

“…Several clinical trials are ongoing regarding the development of novel drugs for use against pathogenesis and for the treatment of AD by inhibiting various targets and inducing several genes and proteins, individually or in combination, as a multitarget approach [19,20]. Multitarget-directed ligands (MTDLs) are thought to be a more effective treatment option than the single-target approach for the management of Alzheimer's disease due to the complex nature of the disease, where several pathways and a variety of proteins are involved in its development [11][12][13]21,22]. Enzyme/protein inhibition using several in silico approaches is the initial choice for screening novel inhibitors for many drug developers [11,12,23].…”

“…Multitarget-directed ligands (MTDLs) are thought to be a more effective treatment option than the single-target approach for the management of Alzheimer's disease due to the complex nature of the disease, where several pathways and a variety of proteins are involved in its development [11][12][13]21,22]. Enzyme/protein inhibition using several in silico approaches is the initial choice for screening novel inhibitors for many drug developers [11,12,23]. Thanks to recent advancements in computing capacity, it has become possible to develop several cheminformatic approaches in order to obtain rapid screening and optimization of chemical entities [24][25][26][27].…”