Multifunctional effect of flavonoids from Millettia brandisiana against Alzheimer's disease pathogenesis

Puguh Novi Arsito; Pornthip Waiwut; Chavi Yenjai; Supakorn Arthan; Orawan Monthakantirat; Natsajee Nualkaew; Pitchayakarn Takomthong; Chantana Boonyarat

doi:10.1016/j.heliyon.2023.e21894

Multifunctional effect of flavonoids from Millettia brandisiana against Alzheimer's disease pathogenesis

Heliyon. 2023 Nov 8;9(11):e21894. doi: 10.1016/j.heliyon.2023.e21894. eCollection 2023 Nov.

Authors

Puguh Novi Arsito^{1

2}, Pornthip Waiwut³, Chavi Yenjai⁴, Supakorn Arthan⁵, Orawan Monthakantirat¹, Natsajee Nualkaew¹, Pitchayakarn Takomthong¹, Chantana Boonyarat^{1

6}

Affiliations

¹ Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.
² School of Pharmacy, Faculty of Medicine and Health Sciences, Universitas Muhammadiyah Yogyakarta, Yogyakarta, 55183, Indonesia.
³ Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand.
⁴ Natural Products Research Unit, Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen, 40002, Thailand.
⁵ Program of Chemistry, Faculty of Science and Technology, Sakon Nakhon Rajabhat University, Mueang District, Sakon Nakhon, 47000, Thailand.
⁶ Center for Research and Development of Herbal Health Products, Khon Kaen University, Khon Kaen, 40002, Thailand.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and neuronal death. Fifteen flavonoids from Millettia brandisiana were evaluated for the multifunctional effect against AD pathogenesis, including butyrylcholine esterase (BuChE) inhibition, anti-amyloid beta (Aβ) aggregation and neuroprotection against hydrogen peroxide (H₂O₂) toxicity in differentiated human neuroblastoma SH-SY5Y cell. To understand the mechanism and structure-activity relationship, binding interactions between flavonoids and the BuChE and Aβ were investigated in silico. Furthermore, drug-likeness properties and ADMET parameters were evaluated in silico using SwissADME and pKCSM tools. All flavonoids exhibit a good drug-likeness profile. Six flavonoids have potency in BuChE inhibition, and four flavonoids show potency in anti-Aβ aggregation. Flavonoids with the 6″,6″-dimethylchromeno- [2″,3″:7,8]-flavone structure show a favorable multifunctional effect. In silico analysis showed that flavonoids can bind in various positions to the catalytic triad, anionic site, and acyl pocket. In Aβ_1-42, potential flavonoids can attach to the central hydrophobic region and the C terminal hydrophobic and interfere with Aβ interchain hydrogen binding. When compared together, it can inhibit multifunctional action with a favorable ADMET parameter and drug-likeness profile. In addition, candidine can prevent neuronal damage in differentiated SH-SY5Y neuroblastoma cells induced by H₂O₂ in a dose-dependent manner.

Keywords: ADMET; Amyloid beta; Butyrylcholine esterase; Drug-likeness properties; Molecular docking; Multi-mode of action; Neuroprotection; Structure-activity relationship.