|
 
 |
| ORIGINAL ARTICLE |
|
| Year : 2022 | Volume
: 6
| Issue : 2 | Page : 230-242 |
|
A comparative molecular docking study of crocetin with multiple receptors for the treatment of alzheimer's disease
Dhanashree Sharadchandra Kherade, Vrushali Sachin Tambe, Anupa Dnyaneshwar Wagh, Prajakta Bhushan Kothawade
Department of Pharmaceutical Chemistry, PES Modern College of Pharmacy (For Ladies), Pune, Maharashtra, India
| Date of Submission | 06-Jan-2022 |
| Date of Acceptance | 20-Mar-2022 |
| Date of Web Publication | 17-Jun-2022 |
Correspondence Address:
Vrushali Sachin Tambe
PES Modern College of Pharmacy (For Ladies), Moshi, Pune - 412 105, Maharashtra
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/bbrj.bbrj_6_22
Background: Crocetin, an active constituent derived from Crocus sativus L. and Gardenia jasminoides, has shown to have multiple pharmacological activities such as memory booster, anti-oxidants, anti-inflammatory, and neuroprotective actions. Clinical trials on Saffron extract and a preclinical trial of Crocetin for neurodegenerative diseases directs probable use of Crocin in Alzheimer's disease (AD). The Crocin metabolizes into Crocetin after administration. The affinity of Crocetin to different receptor for AD on the basis of molecular docking has not yet been investigated. The present study was aimed to identify the affinity of Crocetin with different receptors involved in Alzheimer's pathogenesis by docking. Autodock Tools (MGL Tools), PYMOL, AutoDock Vina, Discovery studio 2021 client and SwissADME were used. Molecular docking simulation showed significant binding affinity of Crocetin to various receptors. It was found to bind significantly with different receptors like Vitamin D receptor (binding energy-7.9 kcal/mol), Receptor for advanced glycation end products (binding energy-7.5 kcal/mol) and NOD-like receptor pyrin domain-containing-3 (binding energy-7.4 kcal/mol). The results obtained suggest the usefulness of Crocetin in AD. Context: In this study, we have investigated the binding affinity of Crocetin on different receptors related to AD by performing molecular docking studies. Aim: Determination of binding affinity of Crocetin with different receptors involved in AD. Settings and Design: Auto dock vina, Pymol, Discovery studio, Auto dock Tools, Chemsketch, Swiss ADME. Methods: Molecular docking. Results: The Crocetin was found to have significant binding affinity to different receptors such as Vitamin D receptor (binding energy-7.9 kcal/mol), receptor for advanced glycation end products (binding energy-7.5 kcal/mol), and NOD-like receptor pyrin domain-containing-3 (binding energy-7.4 kcal/mol). Conclusions: The present study focuses on docking of Crocetin with different receptors related to the treatment of AD. The Crocetin was found to have a significant binding affinity with different receptors like Vitamin D receptor (binding energy-7.9 kcal/mol), Receptor for advanced glycation end products (binding energy-7.5 kcal/mol), and NOD-like receptor pyrin domain-containing-3 (binding energy-7.9 kcal/mol) while it exhibits moderate binding with receptor-like peroxisome proliferator-activated ϒ receptor (binding energy-7.1 kcal/mol), cannabinoid receptors (binding energy-7.1 kcal/mol) and ryanodine receptor (binding energy-7.0 kcal/mol). It showed the best potential to be developed into an anti-Alzheimer's drug due to its binding with multiple targets. From drug likeliness properties it can be seen that Crocetin can be absorbed by the human body and does not violate the Lipinski rule. Limitations of Study: Theoretical predictions are just consultative and have to be carefully verified by in vivo experiments.
Keywords: Alzheimer's disease, binding energy, crocetin, docking, neurodegeneration, receptors, structure etc
How to cite this article:
Kherade DS, Tambe VS, Wagh AD, Kothawade PB. A comparative molecular docking study of crocetin with multiple receptors for the treatment of alzheimer's disease. Biomed Biotechnol Res J 2022;6:230-42 |
How to cite this URL:
Kherade DS, Tambe VS, Wagh AD, Kothawade PB. A comparative molecular docking study of crocetin with multiple receptors for the treatment of alzheimer's disease. Biomed Biotechnol Res J [serial online] 2022 [cited 2023 Apr 1];6:230-42. Available from: https://www.bmbtrj.org/text.asp?2022/6/2/230/347721 |
| Introduction | |  |
Alzheimer's disease (AD) is the type of neurodegenerative disease. It is categorized as a type of dementia. AD most often affects adults above the age of 65.[1] AD is associated with neuronal death throughout the brain which can be extensively enough that regions of the brain appear atrophied compared with the healthy brain. The reasons of the disease are not well understood. Amyloid beta-protein is found in the extracellular space around neurons in a healthy brain but in AD amyloid-beta and tau protein are found in misfolded state.[2] Crocetin, a unique carotenoid with a short carbon chain, is an active compound of Saffron and Gardenia jasminoides.[3] However; crocetin has beneficial against AD but different receptor for AD on basis of molecular docking has not yet investigated.[4]
| Materials and Methods | | |
Selection of ligand (crocetin)
Saffron is used from ancient times for its medicinal activity's.[5] It has shown activity against AD. Crocetin is the active constituent of Saffron. It has a long chain of 20 carbon atom with two carboxylic acid groups on the opposite side as shown in [Figure 1]. The clinical trials on Saffron extract and a preclinical trial of crocetin for neurodegenerative diseases guide possible use of Crocin in AD.[6],[7] It is also well known for its antidepressant, antioxidant, anti-inflammatory, and anticancer properties.[8]
Selection of receptor
The selection of receptors is done based on their relationship with the pathogenesis and treatment of AD from a literature survey. These receptors have shown therapeutic potential in the prevention of AD pathology.[9],[10],[11]
ADME studies
Pharmacokinetic parameter was predicted by using the SWISS ADME website for pharmacokinetic properties, and drug-like nature which is a prerequisite in dosage form development.[12],[13]
Preparation of receptors
Three-dimensional (3D) structures of all receptors were downloaded from protein data bank (PDB).[14] Then the receptor structure was refined using notepad. We removed all heteroatoms other than amino acids like water. The polar hydrogen and Kollman charges were added.
Preparation of ligand
2D structure of Crocetin was prepared using Avogadro software in SDF format. The SDF file of Crocetin was then converted into PDB file by employing PYMOL software.[15]
Docking process
Autodock 4.2.6 and Autodock vina 1.1.2 were used for molecular docking.[16],[17],[18] Receptor and ligands were converted to pdbqt format in Autodock MGL tools. Receptor structure was converted to gray color after converting to pdbqt format. Pdbqt files were then used for molecular docking. The results were split using auto dock vina split.
Active sites for preparation of grid box were searched from literature and also searched from pdbsum database.[19],[20] The dimension of the grid box was set as per the requirement of structure and other parameters were set to default. The grid box size was set at x = 40, y = 40 and z = 40.
After completion of the docking procedure, the most stable confirmation was chosen for further evaluation purposes. H bond, pi-pi bond, aromatic H bond, and electrostatic interactions were observed in the Discovery studio 2021 client.[21] The result of the docking study is given in [Table 1]. | Table 1: Binding energy of crocetin against various receptors involved in Alzheimer's disease
Click here to view |
| Results | | |
ADME analysis
The ADME analysis of crocetin was done on the basis of smiles using the online Swiss ADME program.[22] The ADME properties of crocetin were calculated and are shown in [Table 2]. The different properties were evaluated to justify drug likeliness behavior. Crocetin follows the Lipinski rule of 5. The molar refractivity value was found to be 98.48. This is within the desired range of 40-130, indicating good receptor binding, cellular uptake, and good bioavailability. The polar surface area also confirms good absorption (ideal value <89 Å2). The result shows the values are significant indicating good candidature of crocetin.
| Discussion | | |
Docking results of all the receptors were compared for binding energy, interacting residues, bond type and binding affinity and are listed in [Table 1].
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor (nAchR) receptor was downloaded from PDB with PDB Id 5FJV. The receptor structure was refined with notepad. Chains A, B, C, D were considered for docking. Targeted docking method was used in this research with the coordinate of origin set at x = −6.065, y = 4.804 and z = −1.696. From docking results, we can conclude that active site residues found in nAchR were, ILE (B) 152, PHE (A) 129, HIS (B) 133, THR (B) 132, ARG (A) 49, GLU (B) 112, LYS (B) 136, ALA (A) 130. The carboxylic acid residue of Crocetin form hydrogen bond with HIS (B) 133, THR ARG (A) 49, GLU (B) 112 of the receptor at bond distance of 4.63 Ao, 2.35 Ao, 4.33 Ao, 2.35 Ao and oxygen of crocetin form salt bridge with LYS (B) 136 Ao at bond distance of 2.40Ao as shown in [Figure 2].[23]
Estrogen receptor
The chain A of the Estrogen receptor (PDB ID = 1a52) was used for the study. Targeted docking method was used with the coordinate of origin was set at x = 106.274, y = 15.15, and z = 98.110. From docking results, it was observed that active site residues found in 1a52 were LEU (A) 379, TRP (A) 383, LEU (A) 384, ILE (A) 428, ALA (A) 350, MET (A) 388, HIS (A) 524, GLY (A) 521, LEU (A) 525, LEU (A) 354. Crocetin forms alkyl bond with LEU (A) 384, ILE (A) 428, ALA (A) 350, MET (A) 388, LEU (A) 525, LEU (A) 354 with bond length 5.04 Ao, 4.95 Ao, 3.33 Ao, 4.83 Ao, 3.79 Ao, 4.19 Ao and the carboxyl group forms conventional hydrogen bond with LEU (a) 379 Ao, GLY (A) 521 Ao, HIS (A) 524 Ao with bond length 2.12 Ao, 2.25 Ao, 2.19 Ao as shown in [Figure 3].[24],[25],[26] | Figure 3: Crocetin with estrogen receptor with embedded crocetin complex structure of crocetin with estrogen receptor
Click here to view |
Ryanodine receptor
The chain A of ryanodine receptor (PDB ID = 4erv) was docked with Crocetin at the most stable site. In this targeted docking method, the coordinate of origin was set at x = 47.124, y = 17.169 and z = 9.745. From docking results, we can conclude that active site residues found in 4erv were TYR (A) 2621, LYS (A) 2783, SER (A) 2671, PRO (A) 2671, TRP (A) 2670, ILE (A) 2746, and LYS (A) 2779. Crocetin forms conventional bond with LYS (A) 2783, SER (A) 2671, PRO (A) 2671 bond length 2.98 Ao, 2.04 Ao, 2.17 Ao, and Alkyl bond with ILE (A) 2746, and LYS (A) 2779 with bond length 4.60 Ao, 3.65 Ao as shown in [Figure 4].[27]
Gamma-aminobutyric acid receptor
The affinity of Crocetin with chain A of Gamma-Aminobutyric Acid receptor (PDB ID = 4cof) was studied. The coordinate of origin was set at x=-1.053, y =-22.862 and z = 87.685 during this study. From docking results, it can be seen that active site residues found in 4cof were LEU (A) 20, LEU (A) 83, VAL (A) 87 and VAL (A) 16. Crocetin forms Alkyl bond with LEU (A) 20, LEU (A) 83, VAL (A) 87 and VAL (A) 16 with bond length 4.63 Ao, 4.35 Ao, 4.75 Ao, 4.14 Ao, 3.82 Ao and oxygen atom of carboxylic acid forms conventional hydrogen bond with LEU (A) 20 with bond length 2.39 Ao as shown in [Figure 5].[28] | Figure 5: Docked complex of the gamma-aminobutyric acid receptor with crocetin
Click here to view |
Receptor for advanced glycation end products
Docking analysis of Crocetin with Chain N of Receptor for advanced glycation end products (PDB ID = 3O3U) was performed at the most stable site. In Targeted docking method, the coordinate of origin was set at x = 19.898, y = 17.096 and z = 69.191. The active site residues were found in 3o3u were TRP (N) 230, TYR (N) 210, LYS (N) 297, TYR (N) 155, PHE (N) 156, TRP (N) 62, ASP (N) 65, TRP (N) 340, PRO (N) 154.Oxygen atom of Crocetin forms Pi-alkyl bond with TRP (N) 230, TYR (N) 210, TYR (N) 155, PHE (N) 156 with bond length 4.64 Ao, 4.92 Ao, 4.11 Ao and 4.80 Ao, carboxylic acid form conventional hydrogen bond with TRP (N) 230, TYR (N) 210, TRP (N) 62 and ASP (N) 65 with bond length 1.81 Ao, 2.46 Ao and 2.35 Ao as shown in [Figure 6].[29] | Figure 6: Receptor for advanced glycation end products docked with crocetin
Click here to view |
Vitamin D receptor
Chain A of Vitamin D receptor (PDB ID = 5owd) was docked with crocetin at the most stable site. Targeted docking method was used in this research with the coordinate of origin was set at x = −35.249, y = 18.182, and z = −2.414. From docking results, we can conclude that active site residues found in 5owd were SER (A) 285, AGR (A) 302, HIS (A) 333, LEU (A) 440, ALA (A) 259, TYR (A) 427, LEU (A) 430, HIS (A) 423, LEU (A) 337, MET (A) 300, VAL (A) 262, ILE (A) 296, LEU (A) 261, TYR (A) 323, TRP (A) 314, CYS (A) 316, TYR (A) 179, PHE (A) 182, TYR (A) 175. Crocetin form alkyl bond with LEU (A) 440, LEU (A) 430, LEU (A) 337, MET (A) 300, VAL (A) 262, ILE (A) 296, LEU (A) 261, CYS (A) 316 with bond length 4.89 Ao, 4.30 Ao, 4.83 Ao, 5.34 Ao, 4.59 Ao, 5.32 Ao, 4.64 Ao, 4.75 Ao and carboxylic acid form salt bridge with ARG (A) 302 with bond length 2.20 Ao as shown in [Figure 7].[30]
Cholesterol receptors (3GKI)
The affinity of Crocetin with Chain A of Cholesterol receptors (PDB ID = 3GKI) was analyzed. Targeted docking method was used in this research with the coordinate of origin was set at x=-28.612, y =-43.823 and z = 6.47. From docking results, we can conclude that active site residues found in 3 gki were CYS (A) 109, CYS (A) 63, ASN (A) 106, GLU (A) 110, ASN (A) 222, PHE (A) 66, PHE (A) 68, PRO (A) 115, SER (A) 72, and PRO (A) 48. Carboxylic acid from Crocetin form conventional hydrogen bond with ASN (A) 106, ASN (A) 222, and SER (A) 72 with bond length 2.70 Ao, 2.13 Ao, 2.36 Ao and Carboxylic acid also form Unfavourable Negative–Negative bond as shown in [Figure 8].[31] | Figure 8: Complex structure of crocetin docked with cholesterol receptor
Click here to view |
Toll-like receptors
Chain A of toll-like receptors (PDB ID = 2AOZ) was docked with Crocetin at most stable site. Targeted docking method was used in this research with the coordinate of origin was set at x = 33.709, y = −8.725 and z = 14.306. From docking results, we can conclude that active site residues found in 2aoz are PHE (A) 304, TYR (A) 302, ASN (A) 252, TYR (A) 326, ARG (A) 325, LYS (A) 382, HIS (A) 359.Crocetin form Alkyl bond with ARG (A) 326, LYS (A) 382 with bond length 5.24 Ao, 4.14 Ao Carboxyl group forms conventional hydrogen bond with ASN (A) 252 and HIS (A) 359 with bond length 3.23Ao and 3.12 Ao as shown in [Figure 9].[32]
Chemokine receptors
Chain A of chemokine receptors (PDB ID = 6AKY) was evaluated for it affinity with Crocetin at the most stable site. The coordinate of origin was set at x = −4.2377, y = 15.9297 and z = 21.186. It was seen that the active site residues in 6aky are TYR (A) 108, ALA (A) 29, ALA (A) 90, TYR (A) 176, LYS (A) 26, TYR (A) 89, LEU (A) 33, TYR (A) 37, MET (A) 287 and TRP (A) 86. Carboxylic group of Crocetin form conventional hydrogen bond with bond length 2.40 Ao. Crocetin forms alkyl bond with ALA (A) 29, ALA (A) 90, MET (A) 287 bond length 3.49Ao, 3.75Ao and 4.51 Ao. LYS (A) 26 Ao shows attractive charges with bond length 4.10 Ao as shown in [Figure 10].[33]
Glucocorticoid receptors
Glucocorticoid receptors (PDB ID = 4P6X) with Chain A was considered for analysis purpose. Targeted docking method was used in this research with the coordinate of origin set at x = 3.996, y = 30.292 and z = −8.38. From docking results, we can conclude that active site residues found in 4p6x are SER (A) 650, TYR (A) 648, HIS (A) 645, ASN (A) 731, LEU (A) 647 and ALA (A) 618. Carboxylic acid group of Crocetin form conventional Hydrogen bond with SER (A) 650, ASN (A) 731, ALA (A) 618 with bond length 2.93 Ao, 2.76 Ao and 2.82 Ao as shown in [Figure 11].[34]
G-protein-coupled receptor 40
Chain A of G-protein-coupled receptor 40 (PDB ID = 4PHU) was docked with Crocetin. Targeted docking method was used in this research with the coordinate of origin was set at x=-37.981, y =-2.775, and z = 61.139. The active site residues found in 4phu are LEU (A) 148, LEU (A) 158, SER (A) 77, PRO (A) 80, VAL (A) 81, PHE (A) 142, VAL (A) 84, LEU (A) 135, ALA (A) 83, LEU (A) 171, PHE (A) 87. Carboxyl group of Crocetin form conventional hydrogen bond with LEU (A) 148 with bond length 2.48 Ao as shown in [Figure 12].[35]
Triggered receptor expressed on myeloid cells 2
Chain A of this receptor (PDB ID = 5ELI) at its most stable site was considered for studying binding affinity of Crocetin. Targeted docking method was used in this research with the coordinate of origin was set at x=-61.275, y = 21.142 and z=-17.113. From docking results, we can conclude that active site residues found in 5eli are THR (A) 82, TRP (A) 50, LEU (A) 97, TYR (A) 108, VAL (A) 63, ARG (A) 52, ARG (A) 47, SER (A) 65, and ARG (A) 77. Carboxylic group of Crocetin form conventional hydrogen bond with THR (A) 82, SER (A) 65, ARG (A) 77 with bond length 2.55 Ao, 3.04 Ao, and 3.09 Ao and is forms attractive charges with ARG (A) 47, ARG (A) 77 with bond length 5.28 Ao and 3.09 Ao as shown in [Figure 13].[36] | Figure 13: Triggered receptor expressed on myeloid cells 2 docked with crocetin
Click here to view |
Cannabinoid receptor
Chain R of cannabinoid receptor (PDB ID = 6N4B) was docked at the most stable site with Crocetin. Targeted docking method was used in this research with the coordinate of origin was set at x = 91.409, y = 130.838 and z = 120.169. From docking results, we can conclude that active site residues found in 6n4b are LYS (R) 183, PHE (R) 177, PRO (R) 269, PHE (R) 268, HIS (R) 178, PHE (R) 174, PHE (R) 379, MET (R) 363, LEU (R) 359. Carboxylic group of Crocetin form conventional hydrogen bond with LYS (R) 183 with bond length 2.34 Ao as shown in [Figure 14].[37]
Peroxisome proliferator-activated γ receptor
Chain A of peroxisome proliferator-activated γ receptor (PDB ID = 2P4Y) was chosen for studying binding of crocetin at the most stable site considered for analysis purposes. Targeted docking method was used in this research with the coordinate of origin was set at x = 19.349, y = 7.576, and z = 21.615. The active site residues found in 2p4y are HIS (A) 449, PHE (A) 363, CYS (A) 285, PHE (A) 282, MET (A) 364, LEU (A) 330, TYR (A) 327, LEU (A) 333, ARG (A) 288, LEU (A) 228, and LYS (A) 367. The Carboxylic acid group of Crocetin form conventional hydrogen bond with LEU (A) 228 with bond length 2.41 Ao and it having attractive charges at HIS (A) 449, ARG (A) 288 with bond length 4.83 Ao and 5.16 Ao as shown in [Figure 15].[38] | Figure 15: Complex structure of crocetin docked with peroxisome proliferator-activated γ receptor
Click here to view |
NOD-like receptor pyrin domain-containing
Chain A of NOD-like receptor pyrin domain-containing-3 (PDB ID = 6NPY) was docked with Crocetin at the most stable site. Targeted docking method was used in this research with the coordinate of origin was set at x = 83.2688, y = 98.3758, and z = 92.0662. From docking results, we can conclude that active site residues found in 6npy are ARG (A) 349, PHE (A) 309, GLU (A) 304, GLU (A) 525, GLU (A) 561, TRP (A) 476, TYR (A) 532, ILE (A) 475, ARG (A) 643, LEU (A) 551, GLN (A) 620, and PHE (A) 648. Carboxylic group of Crocetin form conventional hydrogen bond with GLU (A) 304, GLU (A) 525, GLU (A) 525 with bond length 2.48 Ao, 2.24 Ao, and 3.05 Ao. It shows unfavorable Negative-negative bond with GLU (A) 304 with bond length 4.12 Ao and it having attractive charges with residues GLU (A) 561, ARG (A) 349, ARG (A) 643 with bond length 4.12 Ao, 4.53 Ao, 4.26 Ao as shown in [Figure 16].[39] | Figure 16: NOD-like receptor pyrin domain-containing-3 docked with crocetin
Click here to view |
Acknowledgments
Authors acknowledge Modern College of pharmacy (for ladies), Moshi, Pune, for providing research facilities.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | |
| 2. | |
| 3. | Khajeh E, Rasmi Y, Kheradmand F, Malekinejad H, Aramwit P, Saboory E, et al. Crocetin suppresses the growth and migration in HCT-116 human colorectal cancer cells by activating the p-38 MAPK signaling pathway. Res Pharm Sci 2020;15:592-601.  |
| 4. | Zhang J, Wang Y, Dong X, Liu J. Crocetin attenuates inflammation and amyloid-β accumulation in APPsw transgenic mice. Immun Ageing 2018;15:24. |
| 5. | Siddiqui MJ, Saleh MS, Basharuddin SN, Zamri SH, Mohd Najib MH, Che Ibrahim MZ, et al. Saffron (Crocus sativus L.): As an Antidepressant. J Pharm Bioallied Sci 2018;10:173-80. |
| 6. | Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, et al. Original Article: Saffron in the treatment of patients with mild to moderate Alzheimer's disease: A 16-week, randomized and placebo-controlled trial. J Clin Pharm Ther 2010;5:581-8. |
| 7. | D'Onofrio G, Nabavi SM, Sancarlo D, Greco A, Pieretti S. Crocus Sativus L. (Saffron) in Alzheimer's disease treatment: Bioactive effects on cognitive impairment. Curr Neuropharmacol 2021;9:1606-16. |
| 8. | |
| 9. | Barros Câmara A. Alzheimer's disease neuroprotection: Associated receptors in neuroprotection – New approaches and prospects. Intech Open 2020. [doi: 10.5772/intechopen. 91918]. |
| 10. | Salawu F, Umar J, Olokoba A. Alzheimer′s disease: A review of recent developments. Ann Afr Med 2011;2:73. |
| 11. | Dhorajiwala TM, Halder ST, Samant LR. Computer-aided docking studies of phytochemicals from plants Salix subserrata and onion as inhibitors of glycoprotein G of rabies virus. Biomed Biotechnol Res J 2019;3:269-76. [Full text] |
| 12. | Muddukrishnaiah K, Vijayakumar V, Thavamani BS, Shilpa VP, Radhakrishnan N, Abbas HS. Synthesis, characterization, and in vitro antibacterial activity and molecular docking studies of N4, N4 '-dibutyl-3,3 '-dinitro-[1,1 '-biphenyl]-4,4 '-diamine. Biomed Biotechnol Res J 2020;4:242-22. |
| 13. | Halder ST, Dhorajiwala TM, Samant LR. Molecular docking studies of filarial β-tubulin protein models with antifilarial phytochemicals. Biomed Biotechnol Res J 2019;3:162-70. [Full text] |
| 14. | |
| 15. | |
| 16. | |
| 17. | Trott O, Olson AJ. AutoDock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31:455-61. |
| 18. | Mujwar S. Computational bioprospecting of andrographolide derivatives as potent cyclooxygenase-2 inhibitors. Biomed Biotechnol Res J 2021;4:446. |
| 19. | Murugan NA, Kumar S, Jeyakanthan J, Srivastava V. Searching for target-specific and multi-targeting organics for COVID-19 in the Drugbank database with a double scoring approach. Sci Rep 2020;10:19125. |
| 20. | |
| 21. | |
| 22. | |
| 23. | Tropea MR, Li Puma DD, Melone M, Gulisano W, Arancio O, Grassi C, et al. Genetic deletion of α7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer's disease-like pathology. Prog Neurobiol 2021;206:102154. |
| 24. | Lee JH, Jiang Y, Han DH, Shin SK, Choi WH, Lee MJ. Targeting estrogen receptors for the treatment of Alzheimer's disease. Mol Neurobiol 2013;49:39-49. |
| 25. | Al-Janabi S, Hussein A, Khadem R, Mahdi FC, AI-Mosawi K, S. AL-Janabi AA, et al. The role of estrogen in breast cancer. Biomed Biotechnol Res J (BBRJ) 2020;4:293-6. |
| 26. | Tamagno E, Guglielmotto M. Estrogens still represent an attractive therapeutic approach for Alzheimer's disease. Neural Regen Res. 2022;17:93-4. doi:10.4103/1673-5374.314295. |
| 27. | Yao J, Liu Y, Sun B, Zhan X, Estillore JP, Turner RW, et al. Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or without Alzheimer's disease-causing gene mutations. Alzheimers Dement 2022. [doi: 10.1002/alz. 12543]. |
| 28. | Jiménez-Balado J, Eich TS. GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer's disease. Semin Cell Dev Biol 2021;116:146-59. |
| 29. | Volpina OM, Koroev DO, Serebryakova MV, Volkova TD, Kamynina AV, Bobkova NV. Proteolytic degradation patterns of the receptor for advanced glycation end products peptide fragments correlate with their neuroprotective activity in Alzheimer's disease models. Drug Dev Res 2021;82:1217-26. |
| 30. | Panza F, La Montagna M, Lampignano L, Zupo R, Bortone I, Castellana F, et al. Vitamin D in the development and progression of alzheimer's disease: implications for clinical management. Expert Rev Neurother 2021;21:287-301. doi: 10.1080/14737175.2021.1873768. Epub 2021 Jan 18. PMID: 33406925. |
| 31. | Samant NP, Gupta GL. Novel therapeutic strategies for Alzheimer's disease targeting brain cholesterol homeostasis. Eur J Neurosci 2021;53:673-86. |
| 32. | Momtazmanesh S, Perry G, Rezaei N. Toll-like receptors in Alzheimer's disease. J Neuroimmunol 2020;348;577362. |
| 33. | Adrián J, Omar C, Jose M S, Martin A, Constanza A, Elena O, et al. Changes in chemokines and chemokine receptors expression in a mouse model of Alzheimer's disease. Int J Biol Sci 2019;15:453-63. doi:10.7150/ijbs.26703. |
| 34. | Pedrazzoli M, Losurdo M, Paolone G, Medelin M, Jaupaj L, Cisterna B, et al. Glucocorticoid receptors modulate dendritic spine plasticity and microglia activity in an animal model of Alzheimer's disease. Neurobiol Dis 2019;132:104568. |
| 35. | Chen JJ, Gong YH, He L. Role of GPR40 in pathogenesis and treatment of Alzheimer's disease and type 2 diabetic dementia. J Drug Target 2019;27:347-54. |
| 36. | Qin Z, Gu M, Zhou J, Zhang W, Zhao N, Lü Y, et al. Triggering receptor expressed on myeloid cells 2 activation downregulates toll-like receptor 4 expression and ameliorates cognitive impairment in the Aβ 1-42-induced Alzheimer's disease mouse model. Synapse 2020;74:e22161. |
| 37. | Manuel I, de San Román EG, Giralt MT, Ferrer I, Rodríguez-Puertas R. Type-1 cannabinoid receptor activity during Alzheimer's disease progression. J Alzheimers Dis 2014;42:761-6. |
| 38. | Parets S, Miralles M, Fiol de-Roque MA, Trujillo-Estrada L, Cabot J, Péter M, et al. Peroxisome Proliferator-Activated Receptor γ is involved in the Neuroprotection Exerted by 2-hydroxydocosahexaenoic Acid against Alzheimer's Disease. Alzheimer's Dement.2021;17(Suppl.9):e054514. [doi: 10.1002/alz. 054514]. |
| 39. | Lim R, Lappas M. NOD-like receptor pyrin domain-containing-3 (NLRP3) regulates inflammation-induced pro-labor mediators in human myometrial cells. Am J Reprod Immunol 2018;79:e12825. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16]
[Table 1], [Table 2], [Table 3]
|
Search Pubmed for