In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer’s Disease: Prospects for Designing New Therapeutics Compound

Abstract

Memory impairment is a result of multiple factors including amyloid-beta (Aβ) accumulation. Several receptors are mediated for Aβ transport and signaling. Moreover, blood lipids are involved in Aβ signaling pathway through these receptors. Mediated blood lipid level by statins aims to regulate Aβ signaling cascade. First, the structure of receptors was taken from the RCSB PDB database and prepared with MGLTools and AutoDock tool 4. Second, the ligand was prepared for docking through AutoDock Vina. The binding affinity was calculated, and the binding sites were determined through LigPlot+ software. Besides, pharmacokinetic properties were calculated through multiple software. Finally, a molecular dynamics (MD) simulation was conducted to evaluate ligands stability along with clustering analysis to evaluate proteins connection. Our molecular docking and dynamic analyses revealed silymarin as a potential inhibitor of acetylcholinesterase (AChE), P-glycoprotein, and angiotensin-converting enzyme 2 (ACE2) with 0.704, 0.85, and 0.83 Å for RMSD along with -114.27, -107.44, and -122.51 kcal/mol for free binding energy, respectively. Moreover, rosuvastatin and quercetin have more stability compared to silymarin and donepezil in complex with P-glycoprotein and ACE2, respectively. Eventually, based on clustering and pharmacokinetics analysis, silymarin, rosuvastatin, and quercetin are suggested to be involved in peripheral clearance of Aβ. The bioactivity effects of mentioned statins and antioxidants are predicted to be helpful in treating memory impairment in Alzheimer’s disease (AD). Nevertheless, mentioned drug effect could be improved by nanoparticles to facilitate penetration of the blood–brain barrier (BBB).

Research Progress on Natural Plant Molecules in Regulating the Blood–Brain Barrier in Alzheimer’s Disease

“…This effect is speculated to be related to the regulation of Aβ active transport across the BBB [180]. Recent research, based on clustering and pharmacokinetic analysis, has confirmed that quercetin plays a role in the peripheral clearance of Aβ [181]. Moreover, Li M T et al [182] investigated the protective effects of quercetin on HBMECs, focusing on cell vitality, migration, angiogenesis, and apoptosis.…”

Major Bioactive Prenylated Flavonoids from Humulus lupulus L., Their Applications in Human Diseases and Structure-Activity Relationships (SAR) – A Review

“…111 According to the recently reported studies, among the in silico results of FDA-approved drugs, the binding energies of donepezil were reported between -19.71 kcal/mol and -8.4 kcal/mol calculated by using various algorithms such as AutoDock Vina, Glide/ SP/XP, and MOE etc. [112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128] Furthermore, docking scores were given as -10.46 kcal/mol and -7.64 kcal/mol for donepezil and rivastigmine, respectively, by using Glide/ SP. 129 In our previously reported study, we calculated induced fit docking (IFD) and quantum polarized ligand docking (QPLD) scores as -12.20 kcal/mol and -9.54 kcal/mol for known inhibitor neostigmine, respectively, against AChE.…”

Neurochemical Ameliorating of the Hippocampus in Dyslipidemic Alzheimer Patients Following Silymarin; a Double-Blind Placebo-Controlled Randomized Clinical Trial

“…Rosuvastatin reduces microglial load and ,inhibits inflammatory factors, and has a high affinity for binding to proteins such as acetylcholinesterase (AChE) and Aβ ( 12 ). Molecular pharmacokinetics analysis studies show that rosuvastatin has a high affinity for binding to proteins such as AChE and amyloid beta (Aβ), and is involved in the clearance of Aβ ( 12 , 13 ). Hu et al (2020) demonstrated that Rosuvastatin 10mg once daily for 6 months significantly alleviated the cognitive impairment progression and the risks of dementia in older hypertensive patients ( 14 ).…”