Neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, are understood as occurring through genetic, cellular, and multifactor pathophysiological mechanisms. Several natural products such as flavonoids have been reported in the literature for having the capacity to cross the blood-brain barrier and slow the progression of such diseases. The present article reports on
Neurodegenerative diseases (NDDs) arise as a progressive loss of neuron structure and function, resulting in muscle weakness and deterioration of the body’s physiological functions [
Phytochemicals are a diversified group of naturally occurring bioactive compounds in plants; they include flavonoids, alkaloids, terpenoids, lignans, and phenols. Since they have a wide range of chemical, biochemical, and molecular characteristics, phytochemicals are of considerable interest for treating NDDs. Phytochemicals are promising candidates for various pathological conditions involving modulation of multiple signal pathways and serving as antioxidant and anti-inflammatory agents [
Flavonoids fit the NDDs profile, and in a process dependent on the suppression of lipid peroxidation, inhibition of inflammatory mediators, modulation of gene expression, and activation of antioxidant enzymes, flavonoids help maintain the endogenous antioxidant status of neurons, protecting them from neurodegeneration [
This article focuses on flavonoids found in the literature for anti-Parkinson and anti-Alzheimer activity, including targets involved in the degenerative process of each disease. Molecular docking studies detail the structural parameters involved that best contribute to the activity of such compounds. This study facilitates knowledge as applied to two NDDs concerning flavonoid structural enhancements and the pharmacophores involved in the receptor-protein complex.
Parkinson’s disease (PD) is the second most common neurodegenerative disease globally and has been increasing considerably without evidence of cure [
To characterize PD, progressive degeneration of dopaminergic (DA) neurons causing depletion of striatal dopamine and formation of Lewy bodies in the substantia nigra (SN) are the principal neuropathological correlations of motor damage in PD. The symptoms include resting tremor, rigidity, bradykinesia, gait difficulty, postural instability, and behavioral problems [
The treatment of PD focuses on carbidopa to replace dopamine, levodopa drugs, monoamine oxidase B inhibitors, dopamine agonists, catechol-o-methyltransferase inhibitors, anticholinergics, and amantadine [
The use of natural products against PD has intensified in recent years, chiefly compounds derived from plants, since they are known to have fewer side effects than synthetic compounds [
Molecular docking studies are based on joining a particular ligand to a receptor region, providing information about conformation, orientation, and organization at the receptor site [
Desideri et al. [
Our research group applied ligand-based-virtual screening together with structure based-virtual screening (docking) for 469 alkaloids of the Apocynaceae family in a study of human AChE inhibitory activity [
Baul and Rajiniraja [
Adenosine receptors are members of the G protein-coupled receptor superfamily and considered potential targets for treatment of numerous diseases. Adenosine binds four types of G-protein receptors known as A1, A2A, A2B, and A3 all with distribution in the brain. A2A has a more specific and abundant distribution in the basal ganglia. This selective distribution for receptors can help guarantee fewer adverse effects and make nondopaminergic antagonists more promising for the treatment of PD [
The A2A adenosine receptor (A2AAR) is highly expressed in the basal ganglia and depends on Gs and other protein interactions for signal interpretation [
Indeed, five A2A receptor antagonists are now in clinical trials (phases I to III) for Parkinson’s disease, and other antagonists have been reported in the literature [
Schwarzschild et al. [
The restriction of striatum region expression contributes to fewer side effects in PD patients [
A 140 amino acid protein,
Among the factors that influence
Recent studies report a mutation of alanine to threonine at position 53 of the protein gene causing a rare and familial form of PD in four families [
Olanow and Brundin [
The enzyme catechol-O-methyltransferase, also known as COMT, is as an important enzyme involved in biochemistry, pharmacology, and genetic mechanisms. Methylation of endogenous catecholamines, as well as other catechols, is catalyzed by the enzyme catechol-O-methyltransferase (COMT). COMT transfers the methyl group of S-adenosylmethionine (SAM) to the
The COMT enzyme has the single domain structure containing
The catechol-O-methyltransferase (COMT) gene encodes an enzyme that performs catecholamine (such as dopamine, epinephrine, and norepinephrine) degradation [
The enzyme monoamine oxidase B (MAO-B) has been reported as a therapeutic target for the treatment of Parkinson’s disease [
MAO’s mechanism of reaction involves oxidative deamination of primary, secondary, and tertiary amines, to the corresponding aldehyde, and free amine with the generation of hydrogen peroxide. As for the aldehyde, this is metabolized by the enzyme aldehydedehydrogenase, producing acids such as 5-hydroxyindole acetic acid (5-HIAA) or dihydroxy-phenyl-acetic acid (DOPAC), metabolites used as MAO activity drugs. MAO also produces hydrogen peroxide, leading to oxidative stress and neuronal cell death [
MAO can be found in two isoforms, known as isoform A and isoform B, with differences that are of great pharmacological importance [
Studies have reported the expression of MAO-B in human brains or more precisely in the substantia nigra of patients affected by PD [
Alzheimer’s disease (AD) is a progressive neurodegenerative disease common in older people (from 60 years of age and upwards). It consists in memory loss and gradual impairment of cognitive function due to mainly cholinergic neuron death, which makes accomplishment of daily activities difficult, leading the patient to dependence for the basic activities of their daily routine. Because the neurological impairment compromises the autonomic nervous system (ANS), it eventually leads to death. [
One of the symptoms of AD is dementia, and according to the World Health Organization (WHO) Bulletin, AD is the main pathology responsible for up to 70% of individuals with dementia. WHO estimates that more than 47 million people suffer from dementia, and more than half are from underdeveloped countries. Alzheimer’s has no cure and its treatment consists of trying to slow the progression of the disease and offer symptomatic relief [
Alzheimer’s is clinically explained by neuronal decreases linked to deficient synthesis of acetylcholine (ACh) involved in memory, learning, and SNA. Thus, studies commonly aim at inhibiting acetylcholinesterase (AChE) to prevent ACh breakdown and consequent loss of memory and cognitive functions [
Bioactive beta-secretase-1 (BACE1) inhibitors are currently being studied as therapeutic targets. BACE1 inhibition prevents the amyloid
In a molecular docking study [
Barai et al. [
2D structure of Alzheimer’s disease inhibitors. (a) Bergenin. (b) 5,7-dihydroxy-4
Das et al. [
Glycogen synthase kinase-3 (GSK-3) is a protein responsible for the addition of phosphate molecules to serine and threonine residues [
GSK3
According to Chinchalongporn et al. [
Two factors are associated with the incidence of Alzheimer’s, the increase of
ACE is a zinc metalloenzyme that helps regulate blood pressure and body fluids, by converting the hormone angiotensin I into angiotensin II, a potent vasoconstrictor which is widely used in cardiovascular disease therapies such as degradation of
BACE1, a
From the literature, we selected the set of 39 flavonoid structure, known for their antioxidant action. The compounds were submitted to molecular modeling and molecular docking tools to provide their important structural information and activity as multitarget compounds. Data for the physicochemical characteristics of the compounds has been reported (Table
Structure, name, structural formula, and molar mass of the flavonoids present in the study.
No. | Structure | Molecular name | Molecular formula | Mass |
---|---|---|---|---|
1 | 3-O-Methylquercetin | C16H12O7 | 316.058 | |
2 | 8-Prenylnaringenin | C20H20O5 | 340.131 | |
3 | Afzelechin | C15H14O5 | 274.084 | |
4 | Ampelopsin | C15H12O8 | 320.053 | |
5 | Aromadendrin | C15H12O6 | 288.063 | |
6 | Aspalathin | C21H24O11 | 452.131 | |
7 | Aurantinidin | C15H11O6 | 287.055 | |
8 | Butin | C15H12O5 | 272.068 | |
9 | Capensinidin | C18H17O7 | 345.097 | |
10 | Chrysin | C15H10O4 | 254.057 | |
11 | Delphinidin | C15H11O7 | 303.050 | |
12 | Di-hydrogossypetin | C15H12O8 | 320.053 | |
13 | Di-hydromorin | C15H12O7 | 304.058 | |
14 | Epicatechin | C15H14O6 | 290.07 | |
15 | Eriodictyol | C15H12O6 | 288.063 | |
16 | Europinidin | C17H15O7 | 331.081 | |
17 | Fisetin | C15H10O6 | 286.047 | |
18 | Fisetinidol | C15H14O5 | 274.084 | |
19 | Fustin | C15H12O6 | 288.063 | |
20 | Epicatechin gallate | C22H18O10 | 442.090 | |
21 | Genistein | C15H10O5 | 270.052 | |
22 | Gossypetin | C15H10O8 | 318.037 | |
23 | Hesperidin | C28H34O15 | 610.189 | |
24 | Hibiscetin | C15H10O9 | 334.032 | |
25 | Homoeriodictyol | C16H14O6 | 302.079 | |
26 | Isosakuranetin | C16H14O5 | 286.084 | |
27 | Luteolinidin | C15H11O5 | 271.060 | |
28 | Meciadanol | C16H16O6 | 304.094 | |
29 | Mesquitol | C15H14O6 | 290.079 | |
30 | Morin | C15H10O7 | 302.042 | |
31 | Norartocarpetin | C15H10O6 | 286.047 | |
32 | Pinocembrin | C15H12O4 | 256.073 | |
33 | Procyanidins | C45H38O18 | 866.205 | |
34 | Rhamnetin | C16H12O7 | 316.058 | |
35 | Robinetidinol | C15H14O6 | 290.079 | |
36 | Rosinidin | C17H15O6 | 315.086 | |
37 | Sakuranetin | C16H14O5 | 286.084 | |
38 | Sterubin | C16H14O6 | 302.079 | |
39 | Taxifolin | C15H12O7 | 304.058 | |
40 | Control 4TG-Aden2A-Parkinson | C17H27N3O15P2 | 575.357 | |
41 | Control CLR01–Parkinson | C42H32O8P2 | 726.658 | |
42 | Control BIA–Parkinson | C16H20N4O2 | 300.360 | |
43 | Control ladostigil-Parkinson | C16H20N2O2 | 272.340 | |
44 | Control rivastigmine-Alzheimer | C14H22N2O2 | 250.337 | |
45 | Control galantamine-Alzheimer | C17H21NO3 | 287.340 | |
46 | Control donepezil-Alzheimer | C24H29NO3 | 379.480 |
All of the structures were drawn in HyperChem for Windows v. 8.0.5 (HyperChem, 2009) [
The cytotoxicity risk study was performed using OSIRIS DataWarrior 4.7.3 [
For Parkinson’s disease, the structures of human adenosine receptor A2A (PDB ID 3UZA, at a resolution of 3.2 Å),
For Alzheimer’s, 4 targets with respect to pathology were analyzed, PDB ID 160 K (resolution of 1.94 Å) the crystal structure of glycogen synthase kinase 3 (GSK-3) with a complexed inhibitor [
All 39 flavonoid structures (in MOL format) were submitted to molecular docking using the Molegro Virtual Docker v. 6.0.1 (MVD) [
Studies in structure-based design have become routine in drug discovery, searching for the best profiles against a disease. Thus, it is possible to analyze and discover various pharmacophoric groups and predict possible activities against a certain target. This study was performed through analysis of the physicochemical properties of drugs, such as TPSA and drug absorption, and using studies related to structure-based protein drug design. Toxicity risks and TPSA data, calculated in Osiris software, are presented in Table
Toxicity data, TPSA, and %ABS calculated on the Osiris tool for flavonoids.
Flavonoids | Toxicity risks | TPSA | %ABS |
---|---|---|---|
3-O-methylquercetin | No | 116.450 | 68.824 |
8-prenylnaringenin | No | 86.990 | 78.9884 |
Afzelechin | No | 90.150 | 77.8982 |
Ampelopsin | No | 147.680 | 58.050 |
Aromadendrin | No | 107.220 | 72.009 |
Aspalathin | No | 208.370 | 37.112 |
Aurantinidin | No | 101.150 | 74.103 |
Butin | No | 86.990 | 78.988 |
Capensinidin | No | 88.380 | 78.508 |
Chrysin | No | 66.760 | 85.967 |
Delphinidin | No | 121.380 | 67.123 |
Di-hydrogossypetin | No | 147.680 | 58.050 |
Di-hydromorin | No | 127.450 | 65.029 |
Epicatechin | No | 110.380 | 70.918 |
Eriodictyol | No | 107.220 | 72.009 |
Europinidin | No | 99.380 | 74.713 |
Fisetin | Mutagenic | 107.220 | 72.009 |
Fisetinidol | No | 90.150 | 77.898 |
Fustin | No | 107.220 | 72.009 |
Epicatechin gallate | No | 177.140 | 47.886 |
Genistein | Mutagenic/tumor/reproductive | 86.990 | 78.988 |
Gossypetin | Mutagenic | 147.680 | 58.050 |
Hesperidin | No | 234.290 | 28.169 |
Hibiscetin | Mutagenic | 167.910 | 51.071 |
Homoeriodictyol | No | 96.220 | 75.804 |
Isosakuranetin | No | 75.990 | 82.783 |
Luteolinidin | No | 80.920 | 81.082 |
Meciadanol | No | 99.380 | 74.713 |
Mesquitol | No | 110.380 | 70.918 |
Morin | Mutagenic | 127.450 | 65.029 |
Norartocarpetin | No | 107.220 | 72.009 |
Pinocembrin | No | 66.760 | 85.967 |
Procyanidin | Reproductive | 331.140 | −5.243 |
Rhamnetin | Mutagenic | 116.450 | 68.824 |
Robinetinidol | No | 110.380 | 70.918 |
Rosinidin | No | 92.290 | 77.159 |
Sakuranetin | No | 75.990 | 82.783 |
Sterubin | No | 96.220 | 75.804 |
Taxifolin | No | 127.450 | 65.029 |
Mutagenicity studies can be used to quantify the role played by various organics in promoting or interfering with the way a drug can associate with DNA. According to the data from the Osiris program, flavonoids present low tendencies to be toxic. There were only six compounds that presented mutagenic toxicity (fisetin, genistein, gossypetin, hibiscetin, morin, and rhamnetin); two presented reproductive toxicity (genistein and procyanidin) and one presented tumor activity (genistein). These compounds present high risk and do not possess good drug profiles.
The molecular docking studies for the flavonoids and the control drugs with the PD targets are presented in Table
Description of energy scores of flavonoids and control compounds on PD target proteins.
Flavonoids | Aden A2A | COMT | MAO-B | |
---|---|---|---|---|
3-O-methylquercetin | −71.095 | −74.901 | −53.659 | −140.763 |
8-prenylnaringenin | −83.692 | −83.012 | −67.998 | −145.425 |
Afzelechin | −61.973 | −70.911 | −51.278 | −107.22 |
Ampelopsin | −60.848 | −74.188 | −53.806 | −134.626 |
Aromadendrin | −53.880 | −66.701 | −45.951 | −123.726 |
Aspalathin | −55.009 | −86.361 | −56.396 | −150.386 |
Aurantinidin | −67.749 | −75.414 | −56.591 | −117.977 |
Butin | −68.355 | −77.949 | −60.034 | −124.25 |
Capensinidin | −84.669 | −87.321 | −71.529 | −140.926 |
Chrysin | −59.594 | −70.872 | −52.576 | −120.287 |
Delphinidin | −70.457 | −82.877 | −68.376 | −126.481 |
Di-hydrogossypetin | −56.359 | −73.612 | −48.949 | −135.483 |
Di-hydromorin | −61.416 | −66.071 | −54.329 | −131.088 |
Epicatechin | −66.996 | −74.661 | −53.054 | −122.78 |
Eriodictyol | −66.790 | −74.167 | −55.545 | −119.801 |
Europinidin | −75.421 | −79.694 | −74.993 | −140.585 |
Fisetin | −67.182 | −79.763 | −64.252 | −130.773 |
Fisetinidol | −64.279 | −72.271 | −59.406 | −118.506 |
Fustin | −59.854 | −76.510 | −56.851 | −135.63 |
Epicatechin gallate | −113.727 | −98.330 | −96.205 | −174.333 |
Genistein | −68.316 | −73.585 | −58.867 | −119.162 |
Gossypetin | −63.019 | −75.620 | −58.446 | −139.059 |
Hesperidin | −101.446 | −89.698 | −65.656 | −181.222 |
Hibiscetin | −71.879 | −75.302 | −60.718 | −137.019 |
Homoeriodictyol | −75.599 | −82.786 | −62.698 | −141.639 |
Isosakuranetin | −65.924 | −71.351 | −49.177 | −131.514 |
Luteolinidin | −65.240 | −80.031 | −57.149 | −122.481 |
Meciadanol | −73.596 | −77.668 | −55.342 | −126.337 |
Mesquitol | −60.219 | −74.776 | −51.753 | −128.058 |
Morin | −70.744 | −84.587 | −59.595 | −139.778 |
Norartocarpetin | −67.527 | −77.898 | −60.514 | −137.774 |
Pinocembrin | −56.707 | −66.573 | −46.254 | −113.423 |
Procyanidin | −98.216 | −130.002 | −85.226 | −88.460 |
Rhamnetin | −69.702 | −83.582 | −49.586 | −142.785 |
Robinetinidol | −62.594 | −78.967 | −51.172 | −125.203 |
Rosinidin | −83.735 | −95.587 | −63.376 | −149.196 |
Sakuranetin | −70.695 | −74.984 | −51.408 | −129.56 |
Sterubin | −69.560 | −77.022 | −56.015 | −141.623 |
Taxifolin | −56.665 | −69.743 | −52.804 | −126.612 |
For the enzyme Aden2A, it was observed that the three flavonoids (epicatechin gallate, hesperidin, and procyanidin) with respective energy values of −113.727 kcal/mol, −101.446 kcal/mol, and −98.216 kcal/mol presented higher affinities when compared to the PDB ligand (4TG).
The flavonoids pre PDB ligand; hydrogen bonds present in hydroxyl groups with residues Asn253, Ala63, His250, His278, and steric interactions were observed for Asn253, Phe168, Trp246, and Leu249 for the flavonoids which presented higher score values. Key interactions were detected at His278, Leu249, and Asn253, being present in all of the flavonoids studied, principally at residue Asn253, because it is also present for the ligand PDB (Figure
Molecular docking of flavonoids at the active site of Aden A2A (PDB: 3UZA),
For the enzyme
Most COMT inhibitors have a catechol ring in their structure, such as entacapone and tolcapone, the most famous COMT inhibitor drugs. In our studies the enzyme COMT also presented flavonoid compound activity, being epicatechin gallate (−96.205 kcal/mol) a stronger interaction than the PDB ligand (BIA = −80.800 kcal/mol). For flavonoid activity, interactions with the active site presented eight residues, such as Asp141, Asn170, Lys144, Met40, and Glu199, forming hydrogen interactions with the catechol portions of the flavonoids. Residues Asn170, Glu199, Trp38, Leu198, Asp141, and Trp143 presented hydrophobic interactions with the hydroxyl portions of the flavonoids (Figure
MAO-B enzyme docking was performed at the two active PDB ligand sites. At the active site we saw that all of the flavonoids in the study were bound to the enzyme at both sites, with the same prevalence of compounds and presenting very close values at both sites. We also observed that the B subunit presents greater interaction with the compounds than subunit A (Table
We observed that the interactions between flavonoids and the study proteins occurred close to the hydroxyl groups present in the ligand structure and a strong interaction with the catechol ring. It was also observed that molecules with greater molecular mass, and electron-donating hydrophilic hydroxyl groups in ring position B, were more reactive with the enzyme, this, given the greater number of steric and electrostatic interactions with the catalytic site. The observations led to the hypothesis that such clusters can be viewed as possible pharmacophores for the development of anti-PD drugs.
Our screening results (yielding the best values against the four studied proteins) indicated that 8-prenylnaringenin, europinidin, epicatechin gallate, homoeriodictyol, capensinidin, and rosinidin present structural characteristics which guarantee their potential pharmacological activity against PD.
Molecular docking of the 39 flavonoids was performed to analyze ligand-receptor integration for AD targets; the total interaction energy values are presented in Table
Energy scores of flavonoids and control compounds against Alzheimer’s disease.
Name | 1Q5K | 2FV5 | 3BKL | 4DJU |
---|---|---|---|---|
3-O-Methylquercetin | −77.844 | −137.815 | −89.583 | −81.959 |
8-Prenylnaringenin | −97.365 | −132.520 | −96.493 | −85.052 |
Afzelechin | −69.480 | −120.893 | −79.982 | −65.259 |
Ampelopsin | −71.079 | −119.645 | −83.823 | −68.341 |
Aromadendrin | −65.678 | −115.123 | −81.374 | −145.179 |
Aspalathin | −91.374 | −153.001 | −125.583 | −92.594 |
Aurantinidin | −77.482 | −113.425 | −84.517 | −60.915 |
Butin | −80.350 | −132.235 | −89.736 | −110.684 |
Capensinidin | −77.262 | −134.112 | −108.407 | −118.415 |
Chrysin | −77.346 | −117.834 | −88.051 | −85.052 |
Delphinidin | −86.937 | −132.828 | −98.687 | −73.381 |
Di-hydrogossypetin | −66.795 | −120.679 | −80.429 | −72.832 |
Di-hydromorin | −67.026 | −121.489 | −87.870 | −71.631 |
Donepezil |
−112.609 | −154.722 | −119.399 | −83.404 |
Epicatechin | −72.393 | −127.619 | −83.552 | −78.328 |
Eriodictyol | −74.681 | −124.042 | −87.631 | −90.944 |
Europinidin | −85.511 | −140.803 | −108.977 | −89.075 |
Fisetin | −81.627 | −139.645 | −95.587 | −73.317 |
Fisetinidol | −74.131 | −116.368 | −83.084 | −65.914 |
Fustin | −74.571 | −116.130 | −80.078 | −74.650 |
Galantamine |
−84.430 | −156.068 | −93.838 | −115.428 |
Epicatechin gallate | −105.952 | −187.352 | −114.841 | −83.154 |
Genistin | −78.990 | −127.356 | −89.509 | −90.625 |
Gossypetin | −69.944 | −142.715 | −84.131 | −79.410 |
Hesperidin | −85.551 | −145.093 | −97.557 | −80.780 |
Hibiscetin | −66.573 | −144.530 | −103.117 | −81.446 |
Homoeriodictyol | −85.345 | −134.677 | −93.198 | −82.368 |
Isosakuranetin | −76.492 | −124.546 | −81.779 | −70.443 |
Luteolinidin | −76.499 | −121.014 | −84.251 | −87.799 |
Meciadanol | −73.882 | −127.300 | −84.290 | −74.119 |
Mesquitol | −81.114 | −130.982 | −92.321 | −80.051 |
Morin | −79.444 | −130.332 | −97.326 | −80.051 |
Norartocarpetin | −79.739 | −128.750 | −99.216 | −106.335 |
Pinocembrin | −67.298 | −113.647 | −81.535 | −56.405 |
Procyanidin | −115.164 | −154.184 | −113.990 | −81.313 |
Rhamnetin | −81.950 | −127.432 | −89.885 | 130.736 |
Rivastigmine |
−76.582 | −121.774 | −85.559 | 186.829 |
Robinetidinol | −86.339 | −124.910 | −95.178 | −136.143 |
Rosinidin | −96.375 | −134.734 | −111.602 | 266.611 |
Sakuranetin | −74.645 | −118.156 | −88.698 | −89.075 |
Sterubin | −85.628 | −124.397 | −91.209 | −145.179 |
Taxifolin | −69.263 | −120.177 | −77.806 | −82.368 |
For the GSK-3 target, two flavonoids (procyanidin and epicatechin gallate) presented better receptor interaction results with respective energy values of −115.164 kJ/mol and− 105.952 kJ/mol. However, procyanidin presents toxicity risks to the reproductive system. Analyzing interactions with the amino acid residues, we perceived hydrogen bonds of hydroxyls at residue Val135, as well as Asp133, and discretely at Arg141, Pro136, and Try134 for most of the studied flavonoids. Comparing the common amino acid residues of the interaction of the complexed ligand with the crystalline target, we noticed the common contribution of two residues with hydrogen bonds, 2 interactions with residue Val135, and 1 interaction with Pro136, leading to the hypothesis that these residues contribute to GSK-3 inhibitory activity.
For the TACE target, three flavonoids presented interaction energies below 150.0000 kJ/mol (epicatechin gallate, procyanidin, and aspalathin) with respective interaction energies of −187.352 kJ/mol, −154.184 kJ/mol, and− 153.001 kJ/mol. In addition to the abovementioned toxicity of procyanidin, there is little possibility for oral absorption since the %ABS = −5.241. For this target the molecules showed an interaction tendency for hydrogen bonding with Try433, Try436, and Pro437. For most of the compounds studied, the ligand when complexed with the PDB presented hydrogen-bonding interactions with residues Gly349, His409, His405, Glu406, Leu348, Gly349, and Asn447.
For the ACE target, thirteen compounds presented better interactions (below the median dock energy for each target studied) and hydrogen bond interactions with at least one of the amino acid residues: Tyr520, His513, Lys511, Tyr523, His353, Glu411, Glu384, and Ala356. Of these, five had molecular docking energies below −100.000 kJ/mol, aspalathin, epicatechin gallate, rosinidin, europinidin, and capensinidin.
Finally, for the BACE1 inhibition study, seventeen molecules presented satisfactory molecular docking energies, of which six (aromadendrin, sterubin, robinetidinol, capensidin, butin, and norartocarpetin) presented energies between −106.335 kJ/mol and −145.179 kJ/mol. The amino acid residues involved in the ligand-receptor interaction, with hydrogen bonds in important residues, Ile187, Glu95, Thr292, Asp289, Phe169, Thy132, Asn98, Trp137, Ser97, and Arg189, appeared with a high number of molecular bonds. In Figure
Molecular docking of flavonoids in the active site of GSK3 (PDB: 1Q5K), TACE (PDB: EFV5), ACE (PDB: 3BKL), and BACE1 (PDB: 4DJU). (a) Docking of flavonoids in the active site of GSK3 (green to procyanidin and yellow to epicatechin gallate). (b) Docking of flavonoids in the active site of TACE (green to epicatechin gallate, yellow to procyanidin, and blue to aspalathin). (c) Docking of flavonoids in the active site of ACE (green to aspalathin, yellow to epicatechin gallate, and blue to procyanidin). (d) Docking of flavonoids in the active site of BACE1 (green to sterubin, yellow to aromadendrin, and blue to robinetidinol).
By cross-checking the virtual screening data of the 39 flavonoids with the best interactions for each chosen PDB target, 7 flavonoids with the best results were obtained and are presented in this research: 8-prenylnaringenin, europinidin, epicatechin gallate, homoeriodictyol, aspalathin, butin, and norartocarpetin.
We conclude that the flavonoids of the study demonstrate potential neuroprotective activity by virtue of binding to certain key targets for Parkinson’s and Alzheimer’s. Based on our molecular docking studies, the flavonoids 8-prenylnaringenin, europinidin, epicatechin gallate, homoeriodictyol, capensinidin, and rosinidin present the best results for Parkinson’s, whereas for Alzheimer’s, the flavonoids 8-prenylnaringenin, europinidin, epicatechin gallate, homoeriodictyol, aspalathin, butin, and norartocarpetin present the best results. With lower and comparable binding energies (compared to crystallized binders), four flavonoids were observed in common for both diseases, presenting interactions and similarities consistent to those reported in the literature. For these flavonoid derivatives, it was observed that having greater flexibility together with hydrophobic hydroxyl groups facilitates interactions with hydrophobic regions of the target protein-binding sites.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors declare that there is no conflict of interest regarding the publication of this paper.
The authors wish to acknowledge the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.