Molecular interaction of Centella asiatica bioactive compounds and Donepezil on Alzheimer’s protein through in silico studies

Hagar Ali Marzouk¹, Syahputra Wibowo², Husnul Khotimah³, Sutiman Bambang Sumitro¹*

¹Department of Biology,Faculty of Mathematics and Natural Science,

Brawijaya University, Malang 65145, East Java, Indonesia.

²Doctoral program, Department of Biology, Faculty of Mathematics and Natural Science,

Brawijaya University, Malang 65145, East Java, Indonesia.

³Department of Pharmacology, Faculty of Medicine, Brawijaya University, Malang 65145, East Java, Indonesia.

*Corresponding Author E-mail: sutiman@ub.ac.id

ABSTRACT:

Alzheimer's disease is a chronic neurodegenerative illness that is one of the most persistent medical concerns with significant social and economic consequences. Current treatments, such as acetyl-cholinesterase inhibitors, only briefly alleviate cognitive decline and do not stop or reverse dementia progression. So the study aimed to illustrate the interaction between Centella asiatica bioactive compounds and Donepezil on Alzheimer’s protein through in silico analysis. The seven bioactive compound, donepezil and okadaic acid were docked with Acetyl-cholinesterase and Beta Secretase proteins, the docking analysis was performed using AutoDock Vina in PyRx 0.8 software and visualized using Discovery studio software. The results showed that the Centella asiatica bioactive compounds and drug have lower binding affinity than Okadaic acid (control ligand). While bioactive components like naringin and stigmasterol have the highest binding affinity to Acetyl-cholinesterase, (-11 kcal/mol, -10.9 kcal/mol) compared with the binding affinity score of donepezil with (-10.1 kcal/mol). While luteolin, and rutin furthermore naringin, showed the lowest binding affinity against Beta Secretase with binding affinity score (-7.6 kcal/mol), compared with the binding affinity of Donepezil with (-6.9 kcal/mol). Besides that, gallic acid, luteolin, and cathecin have (-6.4 kcal/mol, -9.9 kcal/mol, and -10.1 kcal/mol, respectively), but they can cover up 75 percent of the binding site of Okadaic acid in Acetyl-cholinesterase protein, whereas Donepezil can only cover up 25 percent of the binding site of Okadaic acid in Acetyl-cholinesterase. In conclusion, bioactive components from Centella asiatica are more stable against Alzheimer's disease than donepezil. More study is needed to evaluate the efficacy of Centella asiatica bioactive components against Alzheimer's.

KEYWORDS: Anti-Alzheimer’s disease, bioactive compound, binding affinity, centella asiatica, donepezil, molecular docking.

INTRODUCTION:

Alzheimer’s disease (AD) contributes to 60–80% of add up to dementia cases, and it generally affects elder individuals (65 a long time of age or more seasoned). The pathogenesis of AD is ordinarily related with the accumulation of amyloid-β (Aβ) totals and the hyper-phosphorylation of tau proteins, driving to neurofibrillary tangles (NFTs) and synaptic brokenness¹.

Around 35.6 million individuals worldwide are evaluated to be influenced with AD, with a predominance rate of 4.6 million unused cases each year. The predominance rate of AD increments with age: the rate pairs each 5 a long time from 60 a long time of age². While the cause is unknown, genetic components account for 5 to 10% of familial Alzheimer's cases, with the remaining 90 to 95% being random. Being heterozygous or homozygous for the apolipoprotein E4 (apoE4) gene increases the likelihood of getting Alzheimer's. One of toxic chemical that caused AD is okadaic acid (OKA) which can induce both neuro-degeneration and hyper-phosphorylation of tau; acceleration of the Aβ formation, oxidative stress, neuro-inflammation and neurotoxicity³. Efforts to identify a cure for Alzheimer's disease have so far proved futile, and the medications now available to treat the disease have limited efficacy, particularly on the off chance that the infection is in its moderate– severe stage⁴.

Centella asiatica (CA), it also called Gotu Kalo, CA is an essential herbal remedy that is always steady in Chinese, Ayurvedic and Indonesian medicine. This medicinal plant is used to enhance the brain, heal skin disorders, and promote liver and kidney health; it is classified as both a nutraceutical and a cogniceutical. CA is regarded as a nerve and brain cell repairing herb because it has been shown to boost insights and improve memory⁵. Because of having bioactive compounds like (rutin, kaempferol, quercetin, gallic acid, luteolin, catechin, naringin and stigmasterol⁶. CA is extensively used as medication, and in vitro studies using various CA plant extracts revealed that these compounds were capable of suppressing H2O2-induced cell passing, lowering free radical concentrations, and inhibiting β-amyloid cell passing in addition to decreasing Ache activities, proposing a potential part for CA within the treatment and anticipation of Alzheimer’s disease^7,8. Donepezil is used to treat the symptoms of mild to severe Alzheimer's disease. It is a selective and reversible acetylcholinesterase (AChE) inhibitor that works by boosting acetylcholine availability.

Several proteins may have a key role in the pathogenesis of Alzheimer's disease (AD), which play a crucial role in (AD), among of them amyloid beta protein (Aβ)⁹, and acetylcholinesterase (AChE)¹⁰. Aβ produced by cleavage of the protein precursor Abeta (APP) by beta-secretase (BACE1)¹¹ also AchE protein had ability to accelerate the formation of (Aβ) inside the brain and causing AD¹². So that the current drugs that used for AD worked by inhibition of (BACE1) and AchE from formation of (Aβ) protein which is considering as hallmark of diagnosis Alzheimer’s disease. So the study aimed to illustrate the interaction between Centella asiatica (CA) bioactive compounds and Donepezil on Alzheimer’s protein (BACE1 and AchE) in silico study.

METHODS:

Data preparation:

Centella asiatica bioactive compounds that used in this study were (1) catechin, (2) gallic acid, (3) luteolin, (4) naringin, (5) quercetin, (6) rutin, and (7) stigmasterol. We used donepezil as the drug ligand and okadaic acid (OKA) as the control ligand. OKA can be used to induce Alzheimer's disease using the zebra fish as a model¹³.The 3D molecular structure of ligands (bioactive compounds, donepezil, and OKA) were reclaimed from PubChem chemical databases, and the selected ligands were prepared to minimize energy using PyRx's open babel program.

AchE and BACE1 protein structures (1EVE and 2B8L, respectively) were retrieved from the RCSB Protein Data Bank and saved as (.pdb). Using Discovery studio 2016 client software, such proteins were produced by eliminating water molecules and undesirable ligands^14-20, and then storing for further analysis. We also used the STITCH database to analyze the direct effect of CA bioactive compounds, donepezil, and OKA with the two proteins.

Molecular docking and visualization:

PyRx 0.8 software was used to accomplish the molecular docking. The Vina search box for AchE is set to all docking processes with dimensions (Angstrom) x = 67.0630, y = 61.3169, and z = 54.5615, however the center of the box uses x =29.3196, y = 40.4870, and z =10.4594. While the Vina search box for BACE1 is set to all docking processes with dimensions (Angstrom) x = 65.2551, y = 63.0417, and z = 59.0772; the center of the box uses x =5.0286, y = 65.0494, and z =55.8007. The docking results were visualized using the Discovery Studio software²¹.

RESULTS AND DISCUSSION:

Molecular docking:

BACE1 and AChE play a crucial role in the production of neurotoxic β-amyloid (Aβ) and to promote the formation of Aβ fibril, sequentially, are considered the main therapeutic targets for AD. So that it so important to prevent the formation of amyloid protein by inhibition of BACE1²². The molecular docking has been carried out, and the ligands and proteins interactions were noted. The interaction of CA bioactive component, donepezil, and proteins was studied and categorised according on binding affinity. According to this study, naringin has the lowest binding affinity towards AchE protein (-11 kcal/mol), followed by stigmasterol (-10.9 kcal/mol), cathecin (-10.1 kcal/mol), and luteolin (-9.9 kcal/mol), and donepezil (-10.1 kcal/mol). Furthermore, a comparison of bioactive compound binding affinity and donepezil binding affinity against BACE1 protein revealed that naringin, luteolin, and rutin demonstrated lower binding affinity (-7.6 kcal/mol), while querectin and stigmasterol demonstrated binding affinity (-7.2 kcal/mol and -7 Kcal/mol, respectively) comparable to donepezil (-6.9 kcal/mol). This study's binding affinity analysis (kcal/mol) summary is shown in (Table 1).

The major function based on the force field was to observe the binding affinity score. The lower the binding affinity score, the lower the intermolecular strength between the ligand and protein, and the more stable the complex interactions generated²³.

Furthermore, to manifest the direct effect of CA bioactive compounds, donepezil, and OKA with the two proteins (BACE1 and AchE); we analyzed that by using the STITCH database (Figure 1).

The interaction between OkA and AchE protein was shown to be composed of four hydrogen bonds, which were constructed by assuming amino acid residues SER122, GLY118, TRP84, and TYR130 as conventional hydrogen links, carbon hydrogen bonds, and pi-donor hydrogen bonds (Figure 3A). In contrast to donepezil's interaction, which consists of two hydrogen bonds and four hydrophobic bonds, those hydrogen bonds were generated via amino acid residues TYR121 and PHE288 as conventional hydrogen bonds and pi-donor hydrogen bond, respectively, whereas four hydrophobic connections were formed combining the amino acids PHE331 and TRP84 as pi-pi stacked, with the amino acids TYR334 and PHE330 as pi alkyl interaction (Figure 3B). Cathecin produced more hydrogen bonds than donepezil, involving HIS440, TRY130, GLU199, ASN85, TYR121, and SER122 amino acid residues, as well as a hydrophobic bond with TRP84 as a pi-pi stacked and pi-pi T-shaped interaction (Figure 3C). Luteolin interaction with AchE revealed additional hydrogen bonds in amino acid residues ASN85,SER122,TYR121,TYR130,GLU199, and GLY441 as conventional hydrogen bond, carbon hydrogen bond, and pi-donor hydrogen bond, as well as hydrophobic interactions involving TRP84 (Figure 3D). In addition, naringin formed four hydrogen bonds in amino acid residues ASN85, ASP72, TYR70, and TYR121 as conventional hydrogen bonds and pi –donor hydrogen bonds, as well as an electrostatic bond involving ASP72 amino acid residues and two hydrophobic bonds involving TRP84 and TRP279 as pi-pi stacked, pi-pi shaped, and pi-sigma interactions (Figure 3E). Four hydrogen bonds were seen in the interaction between gallic acid and AchE; the amino acid residues engaged in this complex were SER122, TR984, TYR130, and GLU199 as conventional hydrogen bonds, and TRP84 amino acid residues as pi-pi stacked interactions (Figure 3F). Stigmasterol and AchE contact resulted in the formation of eight hydrophobic bonds involving PHE331, TYR334, TRP84, PHE330, TRP279, TYR121, LEU282, and PHE290 as pi-sigma, alkyl, and pi-alkyl interactions (Figure 3G). Three hydrogen bonds, three hydrophobic bonds, and one pi-lone pair interaction were observed between rutin and AchE, with the bonds involving TYR70, SER286, ASP72, TEP279, PHE330, TYR334, and TYR121 amino acid residues (Figure3H). The results showed that the examined bioactive compounds from Centella asiatica had more hydrogen and hydrophobic bonds than donepezil, and that cathecin, gallic acid, and luteolin can cover up to 75 percent of the binding site of OKA in AchE, whereas donepezil can only cover up to 25 percent of the binding site of OKA in AchE. Furthermore, all of the contacts generated by stigmasterol with the protein were hydrophobic bonds; it is abundantly obvious that hydrophobic bonds serve an important role in maintaining the ligands at the binding interface and are also critical for boosting the biological activity of the medicine²⁴. Hydrogen bonding is essential and accounts for the selectivity of ligand protein complexes. Docking and scoring are mostly accomplished by careful examination of bond interactions with -based hydrogen bonds²⁵. Some of the amino acid residues implicated in Donepezil pharmacological interaction with AchE are the same as complex bioactive compounds against AchE protein. This shows that the identical amino acid residue implicated plays a rather substantial function in AchE protein inhibition.

A Okadaic acid

B Donepezil

C Cathecin

D Luteolin

E Naringin

F Gallic acid

G Stigmasterol

H Rutin

Figure 3. Interaction of ligands toward AchE protein, A. Okadaic acid, B. Donepezil, C. Cathecin, D.Luteolin, E. Narinngin, F. Gallic acid, G. Stigmasterol, and H. Rutin

Binding Interaction with BACE1:

Investigated ligands and BACE1 protein was summarized in (Figure 4).

In comparison to donepezil, naringin, luteolin, rutin, quercetin, and stigmasterol had lower binding affinity for BACE1. The amino acid residues PHE108, ASP32, GLN73, SER325, and TYR71 form four hydrogen bonds and two hydrophobic bonds in the interaction of donepezil with BACE1. Conventional hydrogen bonds, carbon hydrogen bonds, and pi-sigma interactions are among the interactions formed (Figure 5A). Naringin interacts with BACE1 via three hydrogen bonds and one electrostatic bond. ARG235 and GLN73 amino acid residues form a conventional hydrogen bond, while THR231 amino acid residues form a carbon hydrogen bond. As a pi-cation interaction, the electrostatic contact established with LYS321 amino acid residues (Figure 5B). Luteolin and BACE1 interaction resulted in the bond of only two hydrogen bonds, which involved THR72 and GLN73 amino acid residues as typical hydrogen bonds (Figure 5C). Quercetin established four hydrogen bonds, one hydrophobic bond, and one electrostatic bond with BACE1; the amino acid residues involved in that interaction were ASP311, VAL309, TRP277, TYP329, PRO308, and ASP318. The kind of interaction was conventional hydrogen bonds, pi-alkyl, and pi-anion (Figure 5D). The five hydrogen bonds, hydrophobic bond, and electrostatic contacts in the rutin complex against BACE1 contained amino acid residues THR72, THR329, TYR198, PRO70, PRO129, ILE126, and ARG128 as typical hydrogen bonds, pi-alkyl, and pi-cation interactions (Figure 5E). The compound of stigmasterol and BACE1 on the other hand created hydrophobic bonds. TYR190, LEU188, TRP189, and HIS181 were the amino acid residues involved in the complex as alkyl, pi-alkyl, and pi-sigma interactions (Figure 5F). Hydrophobic interactions, in addition to the basic function of hydrogen bonding, play an important role in complicated ligand protein interactions. The high number of hydrophobic contacts was examined for the optimization of the complex necessary to improve the ligand's molecular weight, lipophilicity, and ADMET properties^{26,27,28,29,30,31}. A significant number of hydrogen bonding and hydrophobic contacts in CA bioactive compound against the two proteins demonstrate that CA is a more suitable complex ligand-protein rather than the complex between donepezil and two proteins. As a result, utilizing CA as an anti-medicine Alzheimer's is more successful than donepezil.

A Donepezil

B Naringin

C Luteolin

D Quercetin

E Rutin

F Stigmasterol

Figure 5. Interaction of ligands toward BACE1 protein, A. Donepezil, B. Narinngin, C. Luteolin, D. Qquercetin, E. Rutin, and F. Stigmasterol

CONCLUSIONS:

According to the docking analysis results, the combination of AchE protein with two CA bioactive compounds, naringin and stigmasterol, had a lower binding affinity score than donepezil. While the binding affinity of naringin, luteolin, rutin, quercetin, and stigmasterol to BACE1 was higher than those of donepezil complexFurthermore, cathecin and gallic acid can cover up to 75% of the OKA binding site in AchE, but donezepil can only cover up 25% of the OKA binding site in AchE. In addition, the binding relationship generated between bioactive compounds and the two proteins revealed a higher number of hydrogen and hydrophobic interactions. These findings demonstrated that CA bioactive compounds are more stable against AD than donepezil. More study is needed to confirm the efficacy of CA bioactive compounds in the treatment of Alzheimer's disease.

CONFLICT OF INTEREST:

The authors declare no conflicts of interest.

ACKNOWLEDGMENTS:

The authors are appreciative to Brawijaya University for providing the essential research resources.

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Received on 01.11.2021 Modified on 14.12.2021

Research J. Pharm. and Tech 2022; 15(11):4887-4896.

DOI: 10.52711/0974-360X.2022.00821

Ligand (PubChem ID)	Structure	Binding affinity (kcal/mol) AchE BACE1 (1EVE) (2B8L)
Catechin(9064)		-10.1	-6.5
Gallic acid (370)		-6.4	-6
Luteolin (5280445)		-9.9	-7.6
Naringin (442428)		-11	-7.6
Quercetin (5280343)		-9.7	-7.2
Rutin (5280805)		-8.9	-7.6
Stigmasterol (5280794)		-10.9	-7
Donepezil (3152)		-10.1	-6.9
Okadaic acid (446512)		-4.8	-4.5