scholarly journals High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach

2021 ◽  
Vol 14 (9) ◽  
pp. 937
Author(s):  
Danish Iqbal ◽  
Md Tabish Rehman ◽  
Abdulaziz Bin Dukhyil ◽  
Syed Mohd Danish Rizvi ◽  
Mohamed F. Al Ajmi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Natural Product ◽  
High Throughput ◽  
High Throughput Screening ◽  
Dynamics Simulation ◽  
Potential Candidate ◽  
Stable Conformation

Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔGvdW) and non-polar solvation or lipophilic energy (ΔGSol_Lipo) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems.

scholarly journals Prediction of Drug Potencies of BACE1 Inhibitors: A Molecular Dynamics Simulation and MM_GB(PB)SA Scoring

2020 ◽  
Author(s):  
Mazen Hamed
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Electrostatic Interactions ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Brain Disorder ◽  
Kd Values

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1). This enzyme plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer's disease. A group of potent BACE1 inhibitors with known x-ray structures (PDB ID 5i3X, 5i3Y, 5iE1, 5i3V, 5i3W, 4LC7, 3TPP) were studied by molecular dynamics simulation and binding energy calculation employing MM_GB(PB)SA. The calculated binding energies gave Kd values 0.139 µM, 1.39 nM, 4.39 mM, 24.3 nM, 1.39 mM, 29.13 mM and 193.07 nM, respectively. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. The Kd values were compared with experimental values, the structures were discussed in view of the energy contributions to binding. Drug likeness of these inhibitors is also discussed. Accommodation of ligands in the catalytic site of BACE1 is discussed depending on the type of fragment involved in each structure. Molecular dynamics (MD) simulations and energy studies were used to explore the recognition of the selected BACE1 inhibitors by Asp 32, Asp228 and the hydrophobic flap. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity. Interactions with the ligands show a similar binding mode with BACE1. These results help to rationalize the design of selective BACE1 inhibitors.

scholarly journals Effect of Lauric Acid on the Stability of Aβ42-Oligomers

2020 ◽  
Author(s):  
Prabir Khatua ◽  
Asis Jana ◽  
Ulrich H. E. Hansmann
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Molecular Dynamics Simulation ◽  
Lauric Acid ◽  
Cell Membranes ◽  
Dynamics Simulation ◽  
The Stability

AbstractWhile Alzheimer’s disease is correlated with the presence of Aβ fibrils in patient brains, the more likely agents are their precursors, soluble oligomers that may form pores or otherwise distort cell membranes. Using all-atom molecular dynamics simulation we study how presence of fatty acids such as lauric acid changes the stability of pore-forming oligomers built from three-stranded Aβ42 chains. Such a change would alter the distribution of amyloids in the fatty-acid rich brain environment, and therefore could explain the lower polymorphism observed in Aβ-fibrils derived from brains of patients with Alzheimer’s disease. We find that lauric acid stabilizes both ring-like and barrel-shaped models, with the effect being stronger for barrel-like models than for ring-like oligomers.

Copper (Cu2+) Ion Induced Misfolding of Tau Protein R3 Peptide Revealed by Enhanced Molecular Dynamics Simulation

2021 ◽  
Author(s):  
Jing Jing ◽  
Gao Tu ◽  
Hongyan Yu ◽  
Rong Huang ◽  
Xianquan Ming ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Neurodegenerative Diseases ◽  
Significant Role ◽  
Tau Protein ◽  
Dynamics Simulation ◽  
Physiological Conditions ◽  
Intrinsically Disordered

Tau misfolding plays a significant role in some neurodegenerative diseases such as Alzheimer’s disease (AD). It is intrinsically disordered and highly soluble under normal physiological conditions. While the protein will...

Mechanisms of Melatonin Binding and Destabilizing Protofilament and Filament of Tau R3-R4 Domains Revealed by Molecular Dynamics Simulation

2021 ◽  
Author(s):  
Lili Zhu ◽  
Yehong Gong ◽  
Hao Lju ◽  
Gongwu Sun ◽  
Qingwen Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Tau Protein ◽  
Dynamics Simulation ◽  
Pathological Characteristics ◽  
Amyloid Aβ ◽  
Β Amyloid

The accumulations of β-amyloid (Aβ) and tau protein are considered as two important pathological characteristics of Alzheimer's disease (AD). Failures of medicine targeting Aβ have drawn more attention to tau...

scholarly journals Prediction of Drug Potencies of BACE1 Inhibitors: A Molecular Dynamics Simulation and MM_GB(PB)SA Scoring

Computation ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 106
Author(s):  
Mazen Y. Hamed
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Electrostatic Interactions ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Brain Disorder ◽  
Kd Values

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder. One of the important therapeutic approaches of AD is the inhibition of β-site APP cleaving enzyme-1 (BACE1). This enzyme plays a central role in the synthesis of the pathogenic β-amyloid peptides (Aβ) in Alzheimer’s disease. A group of potent BACE1 inhibitors with known X-ray structures (PDB ID 5i3X, 5i3Y, 5iE1, 5i3V, 5i3W, 4LC7, 3TPP) were studied by molecular dynamics simulation and binding energy calculation employing MM_GB(PB)SA. The calculated binding energies gave Kd values of 0.139 µM, 1.39 nM, 4.39 mM, 24.3 nM, 1.39 mM, 29.13 mM, and 193.07 nM, respectively. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. The Kd values are compared with experimental values and the structures are discussed in view of the energy contributions to binding. Drug likeness of these inhibitors is also discussed. Accommodation of ligands in the catalytic site of BACE1 is discussed depending on the type of fragment involved in each structure. Molecular dynamics (MD) simulations and energy studies were used to explore the recognition of the selected BACE1 inhibitors by Asp32, Asp228, and the hydrophobic flap. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, in addition to π–π and van der Waals interactions with the amino acid residues located inside the catalytic cavity. Interactions with the ligands show a similar binding mode with BACE1. These results help to rationalize the design of selective BACE1 inhibitors.

Sign in / Sign up

Export Citation Format

Share Document