INTRODUCTION:

The clinical syndrome of Alzheimer's disease (AD) involving irreversible and progressive brain function impairment due to plaques and tangles found in cerebral cortex^1,2. Alzheimer's features include the impairment of cognitive abilities and intellectual function, along with personality, emotional, and behavioral changes³.

The people suffering from AD become less productive, needing care and assistance in doing the daily activities. Considered to be a highly complex and progressive neurodegenerative disease, AD is one of the leading causes of dementia globally^4,5. Alzheimer's is also considered to be a protein conformational disease caused by a failure in the polymerization and processing of normally soluble protein⁶. Alzheimer's primary pathogenesis is caused by the accumulation of Amyloid β (Aβ) and Tau protein abnormalities⁷. Beta-secretase 1 (BACE1) is required to generate all monomeric forms of Aβ and also involved in this process⁸. Gamma (γ)-Secretase is another protein involved in the formation of Aβ that cleaves the region of the Aβ protein precursor (APP), completing the APP proteolysis process that results in the formation and release of Aβ protein. Aβ deposition, which made up the senile plaques, is often associated with loss of neuronal function and synapses⁹. The protein functions previously described act as a cell surface receptor and carry out physiological functions on the surface of neurons that are involved in neurite growth, neuronal adhesion, and axonogenesis. Through protein-protein interactions, they aided in cell motility and transcriptional regulation³.

The abnormal Tau protein form neurofibrillary tangles inside nerve cells, causing microtubule disintegration, cytoskeleton collapsing, and, as a result, disrupting neural transport system and cell death later. Glycogen synthase kinase (GSK)-3 is involved in this process, being the protein kinase that can modify the additional sites on the Tau molecule. Other contributing factors leading to severe AD are neuroinflammation, oxidative stress, and metal toxicity. Reactive astrocytes-activated microglia and dystrophic neuritis also may found in AD¹⁰.

Curcumin is a chemical compound form found in turmeric. It has a long history of traditional medicine use, mainly in China and India, and spices for food preservation^11,12. Curcumin has been globally well known for its various therapeutic effect such as anti-inflammatory, cholesterol-lowering effect, anti-oxidant, anticancer, and many others¹³. Based on recent studies, curcumin certainly can be developed as a new therapy to treat Alzheimer's^14–16. The authors are interested in further identifying the process and analyzing curcumin's potential effect. In vitro studies have revealed that curcumin inhibited β amyloid oligomerization and β-secretase, which was a result, will lower the Aβ deposition level and the inflammatory response¹⁷. Since Alzheimer disease is a complex disease, it is not only caused by β-amyloid deposition, but many protein have role such as GSK-3 and gamma-secretase¹⁸. Curcumin's other beneficial effect on AD was cholesterol-lowering properties, neurotoxicity prevention, and platelet aggregation inhibitory effect. Considering anti-oxidant properties, for decreases free radicals and protects brain mitochondria from oxidative stress, curcumin may be able to reduced Alzheimer's symptoms caused by oxidation and inflammation^19,20.

MATERIAL AND METHODS:

Protein and Ligand Preparation:

The target proteins were specified based on literature search and Therapeutic Target Database (TTD) screened using the keywords "Alzheimer's" "Target Protein" and "Therapy". Glycogen Synthase Kinase (GSK)-3β (PDB ID: 1Q5K), Beta-secretase 1 (BACE1) (PDB ID: 3IN3), Gamma-secretase in complex with a small molecule (subunit APH-1A, PEN-2, Nicastrin, and Presenilin-1) (PDB ID: 7C91), and Alzheimer's Disease Amyloid A4 Protein (PDB ID: 1AAP) were selected as target proteins, the data were downloaded from Protein Data Bank website in a .pdb file format. The optimization of the target protein was then carried out by separating water residues and ligands using PyMol 2.0 software. The residue which was still present in the target protein will affect the bonding interaction between the protein and the ligand so that it needs to be separated and stored in a .pdb file format before simulating the molecular interactions²¹. Chemical Structure of curcumin as ligands derived from PubChem and was downloaded in a .sdf format. The ligand was optimized using PyRx then the interaction with the target protein was stimulated^22,23.

Pharmacokinetic Profile:

The pharmacokinetic profile of curcumin was analyzed using PreADMET by entering the SMILE formula of curcumin from the PubChem webserver (ID: 969516). The data obtained are Lipinski Rule of Five, Brain Blood Barrier (BBB), Human Intestinal Absorption (HIA), and plasma protein binding²¹.

Binding Affinity Interaction:

Molecular docking study was carried out using PyRx 0.9.5 as the software used for the computational discovery of drug candidates against potential protein targets. In this study, a specific docking was used to determine binding affinity interaction. For GSK-3β docking, a grid box dimension was generated by fixing x, y, z direction to 23.845 x 24.832 x 6.28, and the center of the grid box was fixed at 21 x 21 x 21. For BACE1 docking, a grid box dimension was generated by fixing x, y, z direction to 10.867 x -7.310 x 13.975, and the center of the grid box was fixed at 24 x 24 x 24. For Gamma-secretase docking, a grid box dimension was set at 159.387x 179.156 x 215.173, and the center of the grid box was fixed at 50 x 50 x 50. Then, for Alzheimer's disease, Amyloid A4 Protein docking, a grid box dimension was set at 14.325 x 16.848 x 43.260, and the center of the grid box was fixed at 13 x 13 x 13. All grid box and center based on active site previous studies ^24–27. The docking procedure was repeated three times in order to eliminate blind docking and improve binding affinity accuracy. This in silico analysis will yield the strength of the bonding interaction between the ligand and the target protein. The amino acid residue interactions between ligands and target proteins were visualized using the Discovery Studio software²¹²⁸.

RESULTS AND DISCUSSION:

Drug-likeness of Curcumin:

We used the PreADMET to evaluate the pharmacokinetics of curcumin by inputting the SMILE acquired from Pubcem. The compound was then tested for drug similarity based on the Lipinski Rule of Five criteria on the Lipinski Rule of Five websites (http://www.scfbio-iitd.res.in/software/drugde sign/lipinski.jsp). The criteria are hydrogen bond acceptor (HBA) <10, hydrogen bond donor (HBD) <5, molecular weight <500 Dalton, H₂O partition coefficient (logP) <5, and molar refractivity between 40-130 Å. The compound which meets those principles has a better pharmacokinetics and bioavailability profile in metabolic processes. The Lipinski Rule of Five test results can be seen in Table 1. Curcumin has a good pharmacokinetic cause fullfiled characteristic of Lipinski Rule of Five. So it can be used as drug and given via peroral.

Furthermore, pharmacokinetic tests were carried out using the PreADMET website (http://preadmet.bmdrc.kr/) to predict human intestinal absorption (HIA), the ability of ligands to cross the blood-brain barrier (BBB), and ligand binding with plasma protein (plasma protein binding). The results of the HIA test can be categorized based on the percentage value with the low (0-20%), moderate (20-70%), and high (70-100%) categories.

Table 1. Lipinski Rule of Five Test Results of Curcumin Compound

Compound	Molecule Weight	Hydrogen Donor	Hydrogen Acceptor	Log P	Molar Reactivity	Lipinski Rule
Curcumin	368 g/mol	2	6	3.37	102.02	Yes

Table 2. HIA, BBB and Plasma Protein Binding Score

HIA	BBB	Plasma Protein Binding
94.4%	0.09	88%

The BBB penetration test is based on the BB value (Cbrain / Cblood), where the compounds that can pass the BBB with the high category have a BB value >2.0, the moderate category is 0.1-2.0, and the low category <0.1. The plasma protein binding test is based on the ligand bond's strength with plasma protein, where values >90% indicate a strong bond, while values <90% indicate a weak bond. The weaker the ligand binds with plasma proteins, the higher the ligands' ability to pass through the cell membrane. Pharmacokinetic test results can be seen in Table 2. Based on the pharmacokinetic test, the results of the HIA test were 94.4%, which indicated that this ligand could be absorbed in the intestine in a high category, but the value of 0.09 in the BBB test indicated that the ligand's ability to penetrate BBB was in a low category. The 88% result in the plasma protein binding test showed that the ligands' ability to bind to plasma proteins was in the weak category so that the ligands were able to pass through the cell membrane properly. To enhance BBB penetration, curcumin can be enhanced using nanoparticle technology to transport it more effectively to the Blood Brain Barrier²⁹.

Molecular Docking of Curcumin compounds with various Target Proteins:

Curcumin was obtained from PubChem (ID: 969516) and both pharmacokinetic and pharmacodynamic functions were analyzed. The target protein was found in the Research Collaboratory for Structural Bioinformatics Protein Data Bank, accessed at https://www.rcsb.org/. Table 3 contains information about the target protein, its ID, and the binding affinity results from the molecular docking method.

Table 3. Binding Affinity Interaction between Curcumin and Target Protein

Protein Target	RSCB ID	Binding Affinity (Kcal/mol)
Glycogen Synthase Kinase-3 beta	1Q5K	-8.2
Beta-secretase 1 (Bace1)	3IN3	-8.0
Gamma-secretase in complex with a small molecule (subunit APH-1A, PEN-2, Nicastrin, and Presenilin-1)	7C9I	-6.8
Amyloid A4 Protein	1AAP	-4.9

Molecular docking is a study that analyzes the bonds between ligands and target proteins based on the analysis of their bond energies. The computational study is a strategy to penetrate all aspects to support discovering new drugs at low cost but high effectiveness of screening. The docking used in 3-dimensional structures is often used in Structure-based Drug Design (SBDD)^30,31. The ligand and four target proteins are simulated using PyRx software with a docking center grid, and the dimensions are displayed in Table 3. Curcumin has the ability to bind Glycogen Synthase Kinase (GSK)-3 with a binding affinity of -8.2Kcal/mol, Beta secretase with a binding affinity of -8.0Kcal/mol, Gamma secretase with a binding affinity of -6.8Kcal/mol, and Amyloid A4 Protein with a binding affinity of -4.9Kcal/mol. Protein-ligand interaction with the lowest bond energy is the strongest binding interaction and can affect a protein target's biological activity, so this compound is predicted to have activity in inhibiting GSK-3β. The lowest bond energy will produce a molecule that has a constant temperature and pressure ³². The results of docking using PyRx will be visualized using Pymol and Discovery studio software. Displays two and three-dimensional views of the bonds and the types and strengths of bonds that occur during docking. The results of the visualization, as mentioned below, are attached in Figure 1.

The content of curcumin compounds with the lowest bond energy to the target protein is Glycogen Synthase Kinase (GSK)-3β, with a bond energy of -8.2kcal/mol. The crystal structure of this chemical has been discovered before, and it is bound by a previously reported ligand inhibitor, AR-A014418, which inhibits Tau phosphorylation at a specific GSK3 (Ser-396) location in cells stably expressing the human four-repeat Tau protein²⁴. Additionally, curcumin has been demonstrated previously to fit optimally into the GSK-3β binding pocket via several interactions with essential amino acids and to inhibit GSK-3β in Balb/c mice²⁵. Our research demonstrates and establishes the structure and strength of previously unknown protein-ligand interactions.

A B

C C

Figure 1. Visualization of molecular interaction between Curcumin and protein target. Note: (A) interaction between Curcumin and Amyloid A4 Protein (PDB ID: 1AAP); (B) interaction between Curcumin and Gamma-secretase (PDB ID: 7C9I); (C) interaction between Curcumin and GSK-3β (PDB ID: 1Q5K); (D) interaction between Curcumin and BACE1 (PDB ID: 3IN3)

Protein-ligand interaction was also affected by amino acid residues through its protein target binding domain and the chemical interaction type^22,33,34. Curcumin has the potential to be further analyzed in terms of bond position and the type of chemical interactions formed. We analyze the chemical compounds with the lowest bond energies to determine the molecular interactions and the types of bonds formed using the Discovery Studio software. Curcumin compounds interact with GSK-3β with both conventional and carbon-hydrogen bond type domains, as well as Alkyl bonds. Curcumin binds to the amino acids Asp200, Gly68, Gln185 with hydrogen bonds, and Leu188 and Ile62 with hydrophobic bonds. (Figure 2C). While curcumin bind amyloid A4 protein in Thr11, Ala9 Tyr22, Asp24, and binding creation with Gamma secretase was Asn55, Ser642, Thr647, Thr57, Asp143, as hydrogen bond, while Ala56, Asn55, Ile60, Tyr173, Phe145, Trp548 as hydrophobic bond. Beside curcumin create 4 hydrogen contact and 5 hyrophobic interaction with BACE1. The interaction form in Tyr133, Val131, Leu92, Ala101, Ile180 as hydrophobic bond and trp138, Asn99, Ser97, Thr294 as hydrogen bond.

A B

C D

Figure 2. Type Bond formed between Curcumin and the protein target. Note: (A) bond formed between Curcumin and Amyloid A4 Protein (PDB ID: 1AAP); (B) bond formed between Curcumin and Gamma-secretase (PDB ID: 7C9I); (C) bond formed between Curcumin and GSK-3β (PDB ID: 1Q5K); (D) bond formed between Curcumin and BACE1 (PDB ID: 3IN3)

Bond energy is influenced by the types of chemical bond interactions produced by ligands, such as hydrogen and hydrophobic interactions. The residual amino acid formed by the ligand-protein interaction is critical in determining compound molecules and their potential as drug candidates^25,35,36. Curcumin can interact with GSK-3β with both conventional and carbon-hydrogen bond with the lowest energy binding interaction.

Glycogen synthase kinase-3 (GSK-3) is a widely expressed and constitutively active serine-threonine kinase that regulates a variety of critical cell biology pathways, several of which have been associated with neurodegeneration²⁶. GSK-3 has been proposed to function as a molecular link between Amyloid (Aβ) and Tau in the pathogenesis of Alzheimer's disease. Aβ increases GSK-3 activity, which in turn phosphorylates Tau. On the other hand, GSK-3 regulates the metabolism of amyloid precursor protein (APP) and Aβ production, as well as the death of neurons caused by Aβ.²⁷. Another drug, SAR502250 is effective against biochemical and behavioral indicators of Alzheimer's disease, indicating the therapeutic promise of GSK3 inhibitors in this disease³⁷. In a variety of AD mice models, inhibiting GSK-3 with various drugs can lowers Aβ deposition and neuritic plaque formation, as well as Tau phosphorylation, and ameliorates cognitive impairments as determined by behavioral testing^38,39. GSK-3 exists in two isoforms, GSK3-α and GSK3-β, which are encoded by two distinct genes. GSK3-β is the most prevalent protein in the central nervous system (CNS), and its expression levels are known to rise with age⁴⁰. On the other hand, mice with a conditional overexpression of GSK-3β in the forebrain (Tet/GSK-3 mice) exhibit hyperphosphorylation of Tau at AD-relevant epitopes, which correlates with Tau somatodendritic accumulation in hippocampus neurons. Tet/GSK-3β mice also exhibit a variety of neurodegenerative symptoms, including increased neuronal cell death, reactive astrocytosis, and microgliosis, as well as deficits in spatial learning²⁷. Curcumin acts as a direct inhibitor of GSK-3, so that it can be used as a candidate for therapy in Alzheimer's disease. It can be fundamental used to the next research for curcumin as Alzheimer disease potential treatment.

CONCLUSION:

In sum, the pharmacokinetic analysis in this study reveals the drug-likeness properties of curcumin. Curcumin has a good intestinal absorption property, and it weakly binds to plasma protein. However, curcumin ability for BBB penetration still needs to be modified to improve its pharmacokinetic properties for becoming a novel Alzheimer's disease drug. Moreover, this study analyzed four potential targets for Alzheimer's therapy with curcumin. The result of this study showed that the binding affinity between curcumin and Glycogen Synthetase Kinase (GSK)-3β has the most negative affinity from all potential targets with -8.2 kcal/mol. The researchers discovered that curcumin has the lowest binding energy for GSK3 compared to other candidate protein targets related to Alzheimer's disease, implying that curcumin binds the most strongly to GSK3 and it can be a potential target involving the modification of the additional sites on the Tau molecule in the pathogenesis of Alzheimer's Disease.

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Received on 30.07.2021 Modified on 19.08.2021

Research J. Pharm. and Tech. 2022; 15(7):3069-3074.

DOI: 10.52711/0974-360X.2022.00513