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]
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Figure 1: Crocetin
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
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.
Table 2: Absorption, distribution, metabolism, and excretion parameters
Table 3: Authors contribution
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]
Figure 2: Nicotinic acetylcholine receptor with embedded crocetin
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
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]
Figure 4: Ryanodine receptors docked with crocetin
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
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
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]
Figure 7: Molecular docking of crocetin with Vitamin D receptor
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
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]
Figure 9: Toll-like receptors docked with crocetin
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]
Figure 10: Complex structure of crocetin docked with chemokine receptor
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]
Figure 11: Glucocorticoid receptors docked with crocetin
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]
Figure 12: Crocetin docked with G-protein-coupled receptor 40
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
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]
Figure 14: Cannabinoid receptor docked with crocetin
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
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
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
Authors acknowledge Modern College of pharmacy (for ladies), Moshi, Pune, for providing research facilities.
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