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

Qamar Zia; Md Tabish Rehman; Md Amiruddin Hashmi; Sahabjada Siddiqui; Abdulaziz Bin Dukhyil; Mohammad Z Ahmed; Azfar Jamal; Saeed Banawas; Sami G Almalki; Mohammad Owais; Hamad Qasem Aldhafeeri; Ibrahim M Ibrahim; Wael Alturaiki; Mohamed F AlAjmi; Mohammed Alsieni; Yaser E Alqurashi

doi:10.3389/fnins.2022.915122

Effect of Date Palm (Phoenix dactylifera) Phytochemicals on Aβ_1-40 Amyloid Formation: An in-silico Analysis

Front Neurosci. 2022 Jul 25:16:915122. doi: 10.3389/fnins.2022.915122. eCollection 2022.

Authors

Qamar Zia^{1

2}, Md Tabish Rehman³, Md Amiruddin Hashmi⁴, Sahabjada Siddiqui⁵, Abdulaziz Bin Dukhyil¹, Mohammad Z Ahmed³, Azfar Jamal^{2

6}, Saeed Banawas^{1

2

7}, Sami G Almalki¹, Mohammad Owais⁴, Hamad Qasem Aldhafeeri¹, Ibrahim M Ibrahim⁸, Wael Alturaiki¹, Mohamed F AlAjmi³, Mohammed Alsieni⁸, Yaser E Alqurashi⁶

Affiliations

¹ Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia.
² Health and Basic Sciences Research Center, Majmaah University, Al Majmaah, Saudi Arabia.
³ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁴ Interdisciplinary Biotechnology Unit, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India.
⁵ Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India.
⁶ Department of Biology, College of Science Al-Zulfi, Majmaah University, Majmaah, Saudi Arabia.
⁷ Department of Biomedical Sciences, Oregon State University, Corvallis, OR, United States.
⁸ Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

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 Aβ_1-40 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 Aβ_1-40 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.

Keywords: Alzheimer's disease; Phoenix dactylifera (date palm); drug likeness and bioactivity; molecular docking (MD); phytochemicals (alkaloids/lignans).