INTRODUCTION:

Erectile dysfunction (ED) is a prevalent urological issue affecting men of all ages. It is characterized by the inability to achieve or sustain a sufficiently firm erection for satisfactory sexual intercourse. It's worth noting that ED often has multiple causes. Prompt diagnosis is crucial in distinguishing between psychological and organic origins.¹ Apart from organic factors, depression, performance anxiety, and other sexual concerns can contribute to ED. Cardiovascular conditions are significant contributors, particularly with advancing age, while conditions like diabetes mellitus and metabolic syndrome can disrupt the molecular processes supporting erections, affecting various organ systems and hastening erectile function decline.²

Global statistics indicate that more than 150 million men grapple with ED, a number projected to reach 322 million by 2025.³ Type 2 diabetes mellitus is a major risk factor, with a threefold higher occurrence in diabetic individuals. Key regulatory components for smooth muscle relaxation vital for erectile function include cyclic amino monophosphate, nitric oxide, and cyclic guanosine monophosphate. Disruption in the balance of smooth muscle contraction and relaxation, caused by various factors, leads to impotence.⁴

Certain plant sterols, such as Sitosterol and Campesterol, activate receptors and hormones like testosterone, improving performance and libido. The amino acid arginine is essential for nitric oxide synthesis, enhancing blood flow.⁵ Studies on L-arginase show potential in treating male infertility. Research on Purwoceng extracts suggests they raise testosterone levels. Researchers are continually exploring novel pharmacological solutions.^6-8

Existing treatments for ED, like sildenafil (Phosphodiesterase type 5 inhibitors), are effective but come with side effects like dizziness and headaches. The current focus is on finding new drug targets, aided by bioinformatics, involving structure-based and ligand-based virtual screening techniques.⁹ Molecular docking is crucial, as it characterizes small molecule behaviour in target protein binding sites.¹⁰ It assesses binding strength and receptor-ligand affinity while shedding light on fundamental biochemical processes. This approach aids in drug design and the development of potential treatments for ED.^11,12

MATERIALS AND METHODS:

Molecular Docking protocol:

To investigate the different types of biomolecular interactions and ligand-receptor binding affinities, docking studies were performed. Using the Autodock Vina program,¹³ Autodock vina tools, UCSF Chimera 1.16,¹⁴ Avogadro 1.2.0,¹⁵ Biovia Discovery Studio 2021 client by Dassault Systemes, PyRX¹⁶, and PyMOL, the docking studies were carried out. The crystal structure of the complex of human phosphodiesterase 5 (PDB id:1UDT), arginase (PDB id:4I06), aromatase (PDB id:5JKV), and D2 dopamine receptor (PDB id:6CM4) docking studies were performed.

Protein structures (1UDT, 4I06, 5JKV, and 6CM4) were acquired from RCSB Protein Data Bank in pdb format. UCSF Chimera 1.16 and Auto Dock tools 1.5.7 were utilized for protein preparation, removing secondary chains, non-standard residues, ligands, and water, adding polar hydrogens, and Kollman charges. Ligands, sourced from PubChem in sdf format, underwent optimization in Avogadro to reduce torsional strain.^16,17 Auto Dock tools 1.5.7 added polar hydrogens and Gasteiger charges to ligands, which were then converted into cluster files with BIOVIA Discovery Studio Visualizer 2021 Client. Molecular docking was conducted using PyRx-Virtual Screening Tool and Auto Dock Vina in PyRx software. Grid boxes were maximized to assess biomolecular interactions, and output files were visualized with PyMOL and BIOVIA Discovery Studio Visualizer 2021 Client.

Drug-like properties:

Phytoconstituents were assessed for drug-likeness by inputting canonical SMILES from PubChem into SwissADME. Predicted pharmacokinetic properties and BBB permeability utilized the boiled egg model, considering molar refractivity (MR), log P, molecular weight(MW), HBA, and HBD for Lipinski's rule of five.

ADME/T Studies:

All the selected phytoconstituents were screened for their ADME/T profile, as the canonical smiles were obtained from PubChem, and individual canonical smiles are submitted for ADME/T studies. The following parameters are obtained such as intestinal absorption (human), the volume of distribution (VDss), BBB and CNS permeability, cytochrome P (substrate and inhibitors), total clearance and toxicity studies (AMES test and hepatotoxicity test), were predicted by PKCSM (https://biosig.lab.uq.edu.au/ pkcsm/).¹⁸

RESULT AND DISCUSSION:

Molecular Docking Studies:

a) Selection of ligands and protein:

The chemical components of plants were selected from an already published article, Dr. Duke phytochemical and ethnobotanical databases (U.S. Department of Agriculture).^19,20 Phosphodiesterase type 5 (1UDT) is inhibited and increases the concentration of cGMP causing dilation of corpus cavernosum tissues and penile erection.²¹ Arginase II [4I06] is an enzyme, inhibited to increase the availability of L-arginine, and leads to NO synthesis, thereby increasing erection in males. Aromatase [5JKV] is the enzyme responsible for the synthesis of estrogen from testosterone as it is necessary to inhibit the penile alpha 1 receptors for erection function.²² D2 dopamine receptor [6CM4] is involved in behavioural activity including sexual activity, and hormone attention, enhancing arousal and vigilance.^23,24

b) Molecular docking:

The docking studies were performed with all the 58 chemical constituents of the Fragaria ananassa with phosphodiesterase 5 [1UDT], human arginase [4I06], Human aromatase [5JKV] and D2 dopamine receptor [6CM4]. Lower binding energy in protein-ligand complexes in molecular docking indicates higher complex stability.^25-30

In this investigation, 58 chemical constituents underwent docking with the phosphodiesterase 5 receptor (1UDT), their binding affinities (kcal/mol) and binding residues are documented in table-1. Notably, Beta-carotene, Stigmasterol, Campesterol, and several others exhibited superior binding affinity to the phosphodiesterase 5 receptor when compared to the standard Sildenafil. This implies their potential to elevate cGMP concentration by inhibiting the PDE-5 receptor, leading to penile erection.^31,32

Furthermore, phytoconstituents were subjected to docking with human arginase II (4I06) and human aromatase (5JKV). Ellagic acid, Lutein, and other compounds displayed remarkable binding affinity to arginase II, while Quercetin-3-beta-glucuronide, Campesterol, and Folacin exhibited the highest affinity for aromatase. These findings suggest potential enhancements in aphrodisiac activity and estrogen synthesis inhibition, respectively.^33-35

Moreover, Stigmasterol and Catechin displayed notable affinity toward the D2 dopamine receptor (6CM4), indicating their potential roles in arousal and erection enhancement. Overall, this research underscores the promise of sterols, flavonoids, and phenolic compounds, such as stigmasterol, Kaempferol-3-beta-mono-glucoside, Quercetin-3-beta-glucuronide, and Folacin from Fragaria ananassa, in modulating key aspects of the erectile process.^36,37 The binding affinities for all 58 compounds with their respective proteins are summarized in table 1.

Table 1: Docking score and Bond interactions of ligands with phosphodiesterase 5 (1UDT), human arginase (4I06), aromatase (5JKV) and D2 dopamine receptor (6CM4)

Sl. No.	Protein Ligand	1UDT	4I06	5JKV	6CM4
Sl. No.	Protein Ligand	Binding Affinity (kcal\mol)
1	Alanine	-4.2	-4.3	-4.7	-4.2
2	Alpha-linolenic-acid	-7	-4.9	-7	-6.9
3	Alpha-tocopherol	-8.7	-5.4	-6	-8.3
4	Arginine	-6.2	-6.6	-5.5	-5
5	Ascorbic-acid	-6.1	-6.3	-5.6	-5
6	Aspartic-acid	-5.2	-4.9	-5	-5.2
7	Beta-carotene	-11.2	-7.2	-7.6	-8.3
8	Beta-sitosterol	-10.3	-7.3	-7.6	-8.5
9	Caffeic-acid	-6.7	-7.2	-6.1	-7.2
10	Campesterol	-11	-6.8	-9.7	-8.4
11	Catechin	-9.3	-7	-7.8	-9.4
12	Catechol	-5.4	-5	-5.1	-5.8
13	Chlorogenic-acid	-9.5	-7.4	-7.9	-8
14	Citric-acid	-6.1	-5.9	-6.6	-5.5
15	Cystine	-7	-6.9	-6.1	-5.7
16	Ellagic-acid	-9.2	-8.3	-8.5	-8.6
17	Folacin	-10.5	-8	-9.6	-9.2
18	Gallic-acid	-6.1	-6.5	-5.9	-6.1
19	Gallocatechin	-9	-7.1	-7.7	-8.2
20	Gentisic-acid	-2.9	-3.2	-2.9	-3.1
21	Glutamic-acid	-5.4	-5.3	-5.4	-5.3
22	Glycine	-3.8	-4	-4.1	-3.5
23	Histidine	-6	-6.1	-5.7	-5.1
24	Isoleucine	-5	-4.7	-5.3	-4.4
25	Kaempferol-3-beta-monoglucoside	-10.8	-7.6	-9	-9
26	Lecithin	-6.2	-5.1	-5.1	-5.1
27	Leucine	-5	-4.8	-4.9	-4.6
28	Linoleic-acid	-7	-4.9	-6.5	-6.8
29	Lutein	-9.3	-8.3	-8.8	-8.9
30	Lysine	-5.3	-5.3	-5.2	-5.1
31	Malic-acid	-5.2	-4.8	-5.8	-5.2
32	Malvidin-3,5-diglucoside	-7.7	-10.1	-9.3	-7.7
33	Methionine	-4.8	-4.7	-5	-4.7
34	Neo-chlorogenic-acid	-9.4	-7.3	-8.5	-7.6
35	Niacin (Nicotinic acid)	-5.4	-5.1	-5.7	-5
36	Oleic-acid	-6.8	-4.3	-6.6	-6.7
37	P-coumaric-acid	-6.6	-6.4	-6.6	-7
38	P-hydroxy-benzoic-acid	-5.9	-5..4	-6.1	-6
39	Palmitic-acid	-6.4	-4.6	-6.1	-5.8
40	Palmitoleic-acid	-6.7	-4.9	-5.8	-6.5
41	Pantothenic-acid	-6.1	-6	-6.1	-5.6
42	Pectin	-6.7	-6.9	-5.9	-5.9
43	Pelargonidin-3-glucoside	-10.2	-7.9	-9.2	-9.5
44	Phylloquinone	-9.4	-5.8	-8.4	-8.6
45	Phytate	-4.7	-4.8	-5.4	-5.1
46	Protocatechuic-acid	-8.5	-7.4	-7.3	-8.1
47	Quercetin-3-beta-glucuronide	-10.6	-7.8	-9.7	-8.4
48	Riboflavin	-9.3	-7.2	-8.3	-8
49	Salicylic-acid	-6.3	-5.7	-6	-6.3
50	Serine	-4.7	-4.5	-4.9	-4.2
51	Stearic-acid	-6.7	-4.5	-6.2	-6.5
52	Stigmasterol	-11	-7.7	-9.1	-9.6
53	Thiamin	-6.9	-6.2	-6.7	-6.2
54	Threonine	-5.2	-4.7	-5.2	-4.6
55	Tryptophan	-7.5	-6.3	-6.3	-7.4
56	Valine	-4.7	-4.7	-5.3	-5.4
57	Vanillic-acid	-6.2	-6.1	-5.9	-5.9
58	Vitamin b6	-5.9	-5.6	-5.2	-5.1
59	Sildenafil	-10.1	-7.4	-9.4	-9.3

Figure 1: The 2D interactions of beta-carotene with phosphodiesterase 5 (1UDT), Ellagic acid with human arginase (4I06), quercetin-3-beta-glucuronide with aromatase (5JKV) and stigmasterol with D2 dopamine receptor (6CM4).

Drug Likeliness:

The drug likeliness property for each of Lipinski's rule of five criteria was analyzed for their normal standard values for the 58 chemical constituents of Fragaria ananassa. The chemical constituents with two violations are Beta-carotene, Folacin, Kaempferol-3-beta-mono glucoside, Lutein, and Quercetin-3-beta-glucuronide. Three violations of Lipinski's parameters were detected in the Malvidin-3,5-glucoside. As a result, Figure 3 shows the boiled egg model of the chemical constituents which represents the CNS permeability of the drug components.

ADME/T Studies:

An intestinal absorption rate of 30% or higher in ADME/T characteristics suggests effective absorption. The VDss (volume of distribution) significantly influences pharmacokinetic factors. Compounds with VDss below -1 are poor BBB crossers, while those above 0.3 effectively cross. Fragaria ananassa exhibited varying GI absorption rates (0% to 100%). Some constituents like Aspartic acid, Citric acid, Cystine, Folacin, Gentisic acid, Glutamic acid, Malic acid, Malvidin-3,5-diglucoside, Pectin, Protocatechuic acid, and Quercetin-3-beta-glucuronide displayed limited GI absorption, while others had a favorable distribution volume.

Figure 2: The egg-boiled model of phytochemical constituents of Fragaria ananassa fruit.

Figure 3: The radar plot for oral bioavailability of higher binding scored bioactive molecules with PDE 5 receptor.

In the liver, CYP450 isozymes may metabolize these compounds, all demonstrating favorable total clearance values. Total clearance profoundly impacts the drug excretion rate relative to drug concentration in the body. Assessing toxicity plays a pivotal role in drug selection. Except for Alpha-linolenic-acid, Folacin, Linoleic acid, and Riboflavin, all compounds proved non-toxic. Figure 3 depicts a radar plot of high-affinity components.

CONCLUSION:

In conclusion, all 58 chemical constituents of Fragaria ananassa were docked with four different proteins (1UDT, 4I06, 5JKV, 6CM4) using Autodock Vina. For the successful treatment of erectile dysfunction, potent phosphodiesterase 5, arginase and aromatase inhibitors, and dopamine activators were chosen, and they must possess the drug-likeliness property. These constituents have an affinity towards all the receptors and their docking scores and binding residues are compared with the standard drug sildenafil. Fragaria ananassa fruit’s major constituents such as Beta-carotene, Stigmasterol, Ellagic acid, Lutein, Campesterol, Quercetin-3-beta-glucuronide, and Catechin have the highest affinity, and either by inhibiting and potentiating of these receptors and enzymes. In addition, the pharmacokinetic properties and toxicity studies were evaluated to confirm the safety of these constituents. Further in vitro and in vivo animal studies are required to evaluate the aphrodisiac activity in the treatment of Erectile dysfunction.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank the Management Faculty of Pharmaceutical Sciences, PES University, Bengaluru for their support.

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Received on 15.06.2023 Modified on 17.10.2023

Research J. Pharm. and Tech 2024; 17(7):3315-3319.

DOI: 10.52711/0974-360X.2024.00518