In Silico Docking and In Vitro Approaches towards BACE1 and Cholinesterases Inhibitory Effect of Citrus Flavanones

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, distinctively characterized by senile plaques, neurofibrillary tangles, and synaptic loss, finally resulting in neuronal death. β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) and cholinesterases have been identified as therapeutic targets for AD, and the discovery of their inhibitors is of critical importance for developing preventive strategies for AD. To discover natural multi-target compounds possessing BACE1, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory properties, major citrus flavanones including hesperetin, naringenin, and hesperidin were evaluated. In vitro anti-AD activities were performed via BACE1 and cholinesterases inhibition assays, as well as enzyme kinetic predictions. For the design of potential inhibitors of AD-related enzymes, molecular docking analysis was performed. Based on the biological evaluation, hesperidin demonstrated the best inhibitory properties toward BACE1, AChE, and BChE, with IC50 values of 10.02 ± 1.12, 22.80 ± 2.78, and 48.09 ± 0.74 µM, respectively. Kinetic studies revealed that all tested compounds were found to be noncompetitive inhibitors against BACE1 and cholineseterases. In addition, molecular docking studies of these compounds demonstrated negative binding energies for BACE1, AChE, and BChE, indicating high affinity and tight binding capacity for the target enzymes. The present study suggested that the selected citrus flavanones could act together as multiple inhibitors of BACE1, AChE, and BChE, indicating preventive and therapeutic potential against AD.

The Effect of Sacred Lotus (Nelumbo nucifera) and Its Mixtures on Phenolic Profiles, Antioxidant Activities, and Inhibitions of the Key Enzymes Relevant to Alzheimer’s Disease

“…Inhibitory activities of these enzymes were related to the presence of phenolics in sacred lotus. The most abundant flavonoid, naringenin, was previously reported to exhibit the IC 50 values of 42.66 µM against AChE and >100 µM against BChE [ 43 ]. The second most abundant flavonoid, quercetin, was determined as a stronger inhibitor with the IC 50 value of 3.60 µM against AChE [ 44 ] and 1.2 times higher IC 50 value against BChE than AChE inhibition [ 45 ].…”

“…Phenolics have also been proven to act as BACE-1 inhibitors [ 51 ]. Naringenin was reported to inhibit BACE-1 activity with the IC 50 value of 30.31 µM [ 43 ], while quercetin, a stronger BACE-1 inhibitor, exhibited the IC 50 value of 5.4 µM [ 52 ]. Kaempferol (the IC 50 value of 14.7 µM) and myricetin (the IC 50 value of 2.8 µM) were also reported to effectively inhibit BACE-1 reaction [ 52 ].…”

Phenolic Profiles, Antioxidant, and Inhibitory Activities of Kadsura heteroclita (Roxb.) Craib and Kadsura coccinea (Lem.) A.C. Sm.

“…The major flavonoid contained in Kadsura spp. extract, naringenin, has been previously reported to exhibit AChE inhibitory activity with the IC 50 value of 42.66 µM and BChE inhibitory activity with the IC 50 value of over 100 µM [ 51 ]. It has also been suggested that naringenin could introduce neuroprotective effects in an in vivo study, in which naringenin was found to suppress the activity of AChE, resulting in elevated synaptic cholinergic neurotransmitter level, improved cognitive functions, and prevented memory extinction [ 52 ].…”

“…BACE-1 is, therefore, another key enzyme for AD progression. Naringenin was previously reported to inhibit BACE-1 activity with the IC 50 value of 30.31 µM [ 51 ]. Additionally, an oral administration of naringenin could also improve memory deficits in an Aβ-induced mouse model of AD [ 54 ].…”

Combining In Silico and In Vitro Studies to Evaluate the Acetylcholinesterase Inhibitory Profile of Different Accessions and the Biomarker Triterpenes of Centella asiatica

“…To the best of our knowledge, there are no studies for the evaluation of different CA accessions on AChE inhibitory activity that have been done. It has been reported that a glycosidic compound exhibited a potent neuroprotective activity, improved microglial activation and behavioral dysfunction [40]. Previous studies proved that asiatic acid could reduce the level of corticosterone in a rat's brain, which ameliorates the content of monoamine neurotransmitters and increases the function of hypothalamic-pituitary adrenal for its antidepressant effects [41].…”