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In silico unraveling of molecular anti-neurodegenerative profile of Citrus medica flavonoids against novel pharmaceutical targets

Meysam Dehghan, Fatemeh Fathinejad, Mohammad Hosein Farzaei, and Ebrahim Barzegari

School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran



Received: 2 April 2022  Accepted: 13 September 2022


The traditionally known modulation of the neurological activity and mental health by Citrus medica (citron) is now attributed to its flavonoid compounds because of their widely established neuroprotective effects. By computational testing against a precisely selected set of classic and novel target proteins in major neurodegenerative disorders, this study aims to identify such neuromodulatory phytoligands. Selected drug targets included acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-secretase 1 (BACE1) and CD33 for Alzheimer's disease, monoamine oxidase (MAO), DJ-1 and β-glucocerebrosidase (GBA) for Parkinson's disease, and silent information regulator T1 (SirT1), phosphodiesterase 10A (PDE10A) and transglutaminase (TGA) for Huntington's disease. The interaction of these proteins with twelve C. medica-derived flavonoid compounds was studied by molecular docking, along with a confirmation docking, followed by molecular dynamics simulation and free energy computations for highest-affinity complexes. Outputs were analyzed by visual inspection, bonds profiling, comparative affinities, conventional simulation analyses, interaction thermodynamics and residual energy decomposition. Finally, theoretical pharmacokinetic properties of effective compounds were explored. Four compounds were ranked top against all the ten targets, including hesperidin (against BChE, CD33, MAO, SirT1 and GBA); diosmin (against AChE and PDE10A); rutin (against BACE1 and DJ-1); and naringin (against TGA). Molecular dynamics and free energies confirmed the stability of the interactions, except for PDE10A-diosmin. Pharmacokinetics of all compounds were desirable, but their delivery to the brain tissue was predicted challenging. Practical testing and further studies to optimize the efficiency and distribution of the compounds to the brain are required before designing new neuroprotective formulations based on citron phytoorganics.

Keywords: Citrus medica; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease; Flavonoids; New targets

Full paper is available at

DOI: 10.1007/s11696-022-02496-3


Chemical Papers 77 (1) 595–610 (2023)

Monday, May 20, 2024

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