Effect of Date Palm (Phoenix dactylifera) Phytochemicals on Aβ1−40 Amyloid Formation: An in-silico Analysis

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease and the most prevalent form of dementia. The generation of oxygen free radicals and oxidative damage is believed to be involved in the pathogenesis of AD. It has been suggested that date palm, a plant rich in phenolic compounds and flavonoids, can provide an alternative treatment to fight memory loss and cognitive dysfunction due to its potent antioxidant activity. Thus, we studied the effect of flavonoids present in date palm on Aβ1−40 amyloid formation using molecular docking and molecular dynamics simulation. AutoDock. Myricetin was used as a positive control drug. The flavonoids Diosmetin, Luteolin, and Rutin were found to be potent inhibitors of aggregation (docking energies ≤ −8.05 kcal mol−1) targeting Aβ1−40 fibrils (both 2LMO and 6TI5), simultaneously. Further screening by physicochemical properties and drug-likeness analysis suggested that all flavonoids except Rutin followed Lipinski's rule of five. Rutin was, thus, taken as a negative control (due to its violation of Lipinski's rule) to compare its dynamics with Diosmetin. Diosmetin exhibited the highest positive scores for drug likeness. Since Luteolin exhibited moderate drug-likeness and better absorption properties, it was also included in molecular dynamics simulation. Molecular dynamics of shortlisted compounds (Rutin, Diosmetin, and Luteolin) were performed for 200 ns, and the results were analyzed by monitoring root mean square deviations (RMSD), root mean square fluctuation (RMSF) analysis, the radius of gyration (Rg), and solvent accessible surface area (SASA). The results proved the formation of a stable protein-compound complex. Based on binding energies and non-bonded interactions, Rutin and Luteolin emerged as better lead molecules than Diosmetin. However, high MW (610.5), lowest absorption rate (16.04%), and more than one violation of Lipinski's rule make Rutin a less likely candidate as an anti-amyloidogenic agent. Moreover, among non-violators of Lipinski's rule, Diosmetin exhibited a greater absorption rate than Luteolin as well as the highest positive scores for drug-likeness. Thus, we can conclude that Diosmetin and Luteolin may serve as a scaffold for the design of better inhibitors with higher affinities toward the target proteins. However, these results warrant in-vitro and in-vivo validation before practical use.

Inhibitory Potential of the Ocimum sanctum Phytochemicals on Bruton’s Tyrosine Kinase, a Well-Known Drug Target for Treatment of Chronic Lymphocytic Leukemia: An In Silico Investigation

“…Therefore, in the present study, the ADME analysis of the six top-ranked phytochemicals was performed for further screening, and selection of the best compounds possessing druglike characteristics (Table 2; Supplementary Table S1). Moreover, during ADME analysis, the Lipinski rule of 5 is broadly considered while selecting the drug-like characteristics of a compound [34][35][36]. Based on Lipinski rule of 5 and other ADME analysis filters, three phytocompounds, viz., Molludistin, rosmarinic acid, and Vitexin possessed promising druglike characteristics (Table 2; Supplementary Table S1).…”

Photoinduced electron transfer photodecomposition of 1, 4-Dihydropyridine derivative phototoxic drug Manidipine, Docking and Molecular Dynamic studies

“…These investigations are key to deciphering the intricate interplay between drug compounds and incident light, offering insights into potentially unintended and harmful outcomes [21,22]. Molecular docking and molecular dynamics simulation is very useful computational tools to understand protein-ligand interactions, atomic-level description of the three-dimensional orientation of ligands at the active site of a protein as well as conformational dynamics of active site residues, and molecular stability [23][24][25][26][27][28].…”