NSAIDs as potential treatment option for preventing amyloid β toxicity in Alzheimer’s disease: an investigation by docking, molecular dynamics, and DFT studies

Abstract

Aggregation of amyloid beta (Aβ) protein considered as one of contributors in development of Alzheimer's disease (AD). Several investigations have identified the importance of non-steroidal anti-inflammatory drugs (NSAIDs) as Aβ aggregation inhibitors. Here, we have examined the binding interactions of 24 NSAIDs belonging to eight different classes, with Aβ fibrils by exploiting docking and molecular dynamics studies. Minimum energy conformation of the docked NSAIDs were further optimized by density functional theory (DFT) employing Becke's three-parameter hybrid model, Lee-Yang-Parr (B3LYP) correlation functional method. DFT-based global reactivity descriptors, such as electron affinity, hardness, softness, chemical potential, electronegativity, and electrophilicity index were calculated to inspect the expediency of these descriptors for understanding the reactive nature and sites of the molecules. Few selected NSAID-Aβ fibrils complexes were subjected to molecular dynamics simulation to illustrate the stability of these complexes and the most prominent interactions during the simulated trajectory. All of the NSAIDs exhibited potential activity against Aβ fibrils in terms of predicted binding affinity. Sulindac was found to be the most active compound underscoring the contribution of indene methylene substitution, whereas acetaminophen was observed as least active NSAID. General structural requirements for interaction of NSAIDs with Aβ fibril include: aryl/heteroaryl aromatic moiety connected through a linker of 1-2 atoms to a distal aromatic group. Considering these structural requirements and electronic features, new potent agents can be designed and developed as potential Aβ fibril inhibitors for the treatment of AD.

Breaking Down the Barriers to a Natural Antiviral Agent: Antiviral Activity and Molecular Docking of Erythrina speciosa Extract, Fractions, and the Major Compound

“…The docking protocol used in the present study was therefore validated by docking all native co‐crystallized ligand molecules to their respective proteins (PDB code: 2GV9, 2KI5, 5GMZ, 4A92 and 2HAL). According to the reported method of validation, if the RMSD (root mean square deviation) of the best‐docked conformation is ≤2.0 Å from the experimental one, the used scoring function is deemed to be successful . The RMSD values of the native co‐crystallized ligands after docking were ≤2.0 Å (data not shown), which confirms the reliability of AutoDock 4.2 for docking vitexin into crystal structures of different antiviral drug targets.…”

Effect of Novel Pyrrolo[3,4-d]pyridazinone Derivatives on Lipopolysaccharide-Induced Neuroinflammation

“…The mechanism of NSAIDs may exert a protective effect on neuronal cells by inhibiting cyclooxygenase (COX) activity, especially COX-2, whose expression is strongly induced by inflammatory signals [19]. Several papers describe a relationship between long-term use of NSAIDs and a reduced risk of cognitive impairment, as well as a slower decline in cognitive function [18,30]. However, the mechanism of protective action has not been fully elucidated.…”

“…Some NSAIDs have been shown to be potential inhibitors of β-amyloid fibril formation. They can also activate the expression of other proteins that prevent Aβ aggregation or interact via peroxisome proliferator-activated receptors (PPARs) [18,33,34]. It has also been found that these drugs may affect the processing of amyloid precursor protein (APP) by βand γ-secretases [35].…”

Evaluation of anti-tuberculosis activity of some oxotitanium(IV) Schiff base complexes; molecular docking, dynamics simulation and ADMET studies

“…Frontier molecular orbital features HOMO, LUMO were calculated at the same level of theory. For each of the compounds, HOMO-LUMO gap, hardness (η), softness (S), and chemical potential (μ) were calculated from the energies of frontier HOMOs and LUMOs as previously reported [31] considering Parr and Pearson interpretation [32,33] of DFT and Koopmans theorem [34].…”