Abstract
Background
Urtica dioica (Stinging nettle)has been reported to exhibit various pharmacological activities. In the present study, we aimed to evaluate 24 selected constituents of U. dioica as potent inhibitory agents of human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11beta-HSD1), and human dual specificity phosphatase (hCDC25B) using in silico method.
Methodology
The 24 selected constituents of U. dioica (Stinging nettle) were studied on the docking behavior of hCA-II, h11beta-HSD1, and hCDC25B by using the Webina docking method. In addition to docking, toxicity analysis was also performed using the pkCSM free web server, respectively.
Results
Toxicity analysis has shown that six ligands (25%) of U. dioica (Stinging nettle) are predicted to have hERG II (Human ether-a-go-go-related gene) inhibition activity. The docking analysis showed that afzelin, stigmastane-3, 6-diol, and astragalin of U. dioica have shown the maximum binding energy (-7.2, -9.5, and -8.5 kcal/mol) with the hCA-II, h11beta-HSD1 and hCDC25B, respectively.
Conclusions
Thus, the current finding provides new knowledge about the 24 selected ligands of U. dioica (Stinging nettle) as potent inhibitory agents of human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11beta-HSD1) and human dual specificity phosphatase (hCDC25B).
Keywords: stinging nettle, human dual specificity phosphatase (hcdc25b), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11beta-hsd1), human carbonic anhydrase ii (hca-ii), docking, good health and well-being, urtica dioica
Introduction
Carbonic anhydrase II (CA II) is one of the metalloenzymes that catalases the reversible hydration of carbon dioxide into a bicarbonate ion. It participates in a variety of physiological functions, such as bone reabsorption, respiration, and acid-base balance [1]. CA II deficiency syndrome [a human autosomal recessive disorder] is characterized by i) cerebral calcification, ii) osteopetrosis, and iii) renal tubular acidosis [1]. Studies on naturally occurring phytochemicals that inhibit carbonic anhydrase II activity have been reported to possess therapeutic uses. Similarly, the metabolism of glucocorticoids is catalyzed by two enzymes namely 11 beta-hydroxysteroid dehydrogenases type 1 and 2 (11 beta-HSD1 and 11 beta-HSD2). These enzymes are involved in the inter-conversion of the non-receptor binding inactive form (cortisone) and the receptor binding active form (cortisol). 11 beta-HSD1 is an NADP(H)-the dependent enzyme that converts inactive cortisone to active cortisol in the adipose tissue, brain, liver, and vasculature [2]. An excessive amount of 11 beta-HSD1 enzyme activity has been reported to be involved in metabolic syndrome and its associated cardiovascular complications [2]. Therefore, identifying natural substances that inhibit 11 beta-HSD1 activity has been reported to possess therapeutic applications. Another key enzyme namely, dual specificity phosphatases (DUSP) [CDC25A, CDC25B and CDC25C] are the enzymes that regulate phosphorylation of cyclin-dependent kinases (substrates) during the cell cycle progression. In contrast, (i) cancer, (ii) diabetes, and (iii) neurodegenerative disorders have been associated with dysregulation of DUSP activity [3]. Therefore, identifying natural compounds that inhibit DUSP activity has been reported to possess therapeutically uses.
Urtica dioica (Stinging nettle) belongs to the family Urticaceae, a medicinal perennial flowering plant, commonly referred as “stinging nettle” and in Tamil, it is referred as “Peru-n-kanchori (or) Punnai kasarai.” Urtica species have been used in treatment of rheumatism, sciatica, dandruff, coughs, diabetes, diarrhoea, eczema, gout, fever, haemorrhoids, nosebleeds, scurvy, snake bites, allergies, arthritis, and urinary tract infections [4]. It has also been established that its extracts can successfully reduce inflammation in osteoarthritis, allergic rhinitis, and prostatitis [5-7]. U. dioica has been demonstrated to be an effective treatment for benign prostatic hyperplasia [8,9]. Studies indicate that U. dioica extracts may be useful in lowering symptoms including sneezing, itching, nasal congestion, and allergic rhinitis [10]. In diabetic rats, U. dioica extract successfully lowered blood glucose levels [11]. Extracts from U. dioica showed excellent antioxidant, anti-inflammatory, antiulcer, antiviral, anticancer, antibacterial, antifungal, and insecticide properties [12]. Thus the earlier investigations prompted us to carry out the current study on twenty four selected Urtica dioica constituents which includes afzelin, 2-aminooctadecane-1,3,4-triol, astragalin, 1,2,3-butanetriol, carvacrol, carvone, cycloolivil, estra-1,3,5-trien-ol, ethyl-iso allochalate, kephton, neoolivil, 14-octacosanol, Oxime-methoxy-phenyl, pinanediol, pinene-9,10-diol, pinoresinol, scoparone, 6,6-dimethyl-2-methylenebicyclo [3.1.1] heptane, 1-[3,4-dihydroxyphenyl]-1,2, 4-(3-hydroxyphenyl), 3-[4-hydroxyphenyl], 3-hydroxyacetophenone, stigmastane-3,6-diol and 5,6,7,8-tetrahydroxy-2-(4-hydroxyphenyl)chroman-4-one. These above said Urtica dioica (Stinging nettle) constituents were aimed to study on the docking analysis of human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11 beta-HSD1) and human dual specificity phosphatase (hCDC25B) by employing the Webina docking method. Furthermore, toxicity analysis was also studied using pkCSM free web server.
Materials and methods
Ligand preparation
Chemical structures of the 24 U. dioica (Stinging nettle) ligands namely 1) Afzelin (PubChem ID 5316673); 2) 2-Aminooctadecane-1,3,4-triol (PubChem ID 248575); 3) Astragalin (PubChem ID 5282102); 4) 1,2,3-Butanetriol (PubChem ID 20497); 5) Carvacrol (PubChem ID 10364); 6) Carvone (PubChem ID 7439); 7) Cycloolivil (PubChem ID 5316262); 8) Estra-1,3,5(10)-trien-17B-ol; 9) Ethyl iso- allocholate; 10) Kephton (PubChem ID 5280483); 11) Neoolivil (PubChem ID 9976812); 12) 14-Octacosanol (PubChem ID 5320252); 13) Oxime- methoxy-phenyl; 14) 9, 10-Pinanediol; 15) Pinene-9,10- diol; 16) Pinoresinol (PubChem ID 73399); 17) Scoparone (PubChem ID 8417); 18) 6,6-dimethyl-2-methylenebicyclo[3.1.1] heptane; 19) 1-(3,4-Dihydroxyphenyl)-1,2-propanediol; 20) 4-(3-hydroxypropyl)-2-Methoxyphenol; 21) 3-[4-Hydroxyphenyl]-2-propen-1-ol; 22) 3-Hydroxyacetophenone; 23) Stigmastane-3, 6-diol (PubChem ID 12070151); 24) 5,6,7,8-tetrahydroxy-2-(4-hydroxyphenyl)chroman-4-one were retrieved from PubChem compound database. Unavailable three-dimensional structures were drawn using ChemSketch. Ligands were prepared using ChemDraw 2D and 3D [13]. Thus, these prepared three-dimensional structures were used for further study (Webina docking).
Toxicity analysis
Toxicity analysis was determined for 24 selected ligands of U. dioica (Stinging nettle) using the pkCSM (predicting small-molecule pharmacokinetic properties using graph-based signatures method) free web server [14].
Identification and preparation of target enzyme
The three-dimensional (3D) structure of human carbonic anhydrase II (hCA-II) (PDB ID: 1BCD with a resolution of 1.90 Aᵒ), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11 beta-HSD1) (PDB ID: 2BEL with a resolution of 2.11 Aᵒ) and human dual specificity phosphatase (hCDC25B) (PDB ID: 1QB0 with a resolution of 1.91 Aᵒ) was obtained from Protein Data Bank (PDB). A chain of these enzymes was processed individually by removing other chains, ligands, and crystallographically observed water (H2O) molecules (i.e., water without hydrogen bonds) by utilizing UCSF Chimera software [14].
Docking study
A docking analysis was performed for 24 selected constituents of U. dioica (Stinging nettle) using the Webina (runs based on AutoDock Vina method) free web server [15]. Webina docking method is simple and straight forward one, where it allows users to use various file formats namely mol, pdb and sdf to upload both enzymes (receptors) and ligands input files. Similarly, it also allows users to setting up docking calculations (identifying an appropriate docking box) and analyzing docking output (examining/virtualizing predicted binding poses).
Results
Toxicity analysis has shown that all the ligands of U. dioica do not exhibit any hERG I (human ether-a-go-go-related gene-I) inhibition activity (Table 1).
Table 1. Toxicity analysis of 24 Urtica dioica (Stinging nettle) ligands using the pkCSM free web server.
Note: AMES● -AMES toxicity, hERG I■- Human ether-a-go-go-related gene inhibitor I, hERG II□- Human ether-a-go-go-related gene inhibitor II, ORAT◌- Oral rat acute toxicity (Lethal dose LD50 in mol/kg), HT◊ - Hepatotoxicity, SS*- Skin sensitisation, MT**- Minnow toxicity (log mM).
| Ligand name | AMES● | hERG I■ | hERG II□ | ORAT◌ | HT◊ | SS* | MT** |
| Afzelin | No | No | Yes | 2.61 | No | No | 3.73 |
| 2-Amino Octadecane-1,3,4-triol | No | No | No | 1.78 | No | Yes | 0.40 |
| Astragalin | No | No | No | 2.55 | No | No | 6.74 |
| 1,2,3-Butanetriol | No | No | No | 1.10 | No | No | 3.38 |
| Carvacrol | No | No | No | 2.07 | Yes | Yes | 1.21 |
| Carvone | No | No | No | 1.86 | No | Yes | 1.45 |
| Cycloolivil | No | No | Yes | 2.38 | No | No | 3.44 |
| Estra-1,3,5(10)-trien-17B-ol | No | No | Yes | 2.70 | No | No | 0.54 |
| Ethyl iso- allocholate | No | No | No | 2.05 | No | No | 0.34 |
| Kephton | No | No | Yes | 1.72 | No | No | -5.27 |
| Neoolivil | No | No | No | 2.31 | No | No | 1.78 |
| 14-Octacosanol | No | No | Yes | 1.84 | No | Yes | -3.78 |
| Oxime- methoxy-phenyl | Yes | No | No | 2.13 | No | No | 2.02 |
| 9, 10-Pinanediol | No | No | No | 1.57 | No | Yes | 2.15 |
| Pinene-9,10- diol | No | No | No | 2.01 | No | Yes | 1.74 |
| Pinoresinol | No | No | No | 2.22 | No | No | 1.10 |
| Scoparone | No | No | No | 2.35 | No | No | 1.22 |
| 6,6-dimethyl-2-methylene | No | No | No | 1.70 | No | No | 1.01 |
| 1-[3,4-Dihydroxyphenyl]-1,2-propanediol | Yes | No | No | 1.96 | No | No | 1.90 |
| 4-(3-hydroxypropyl)-2- methoxyphenol | No | No | No | 1.95 | No | Yes | 1.93 |
| 3-[4- Hydroxypheny l]-2-propen-1-ol | No | No | No | 1.80 | No | Yes | 1.71 |
| 3- Hydroxyacetophenone | No | No | No | 1.87 | No | No | 1.69 |
| Stigmastane-3, 6-diol | No | No | Yes | 2.81 | Yes | No | -0.98 |
| 5,6,7,8-tetrahydroxy-2-(4- hydroxyphenyl)chroman-4-one | Yes | No | No | 2.30 | No | No | 1.86 |
Two ligands (carvacrol and stigmastane-3, 6-diol) of U. dioica (Stinging nettle) have been predicted to exhibit a hepatotoxicity nature (Table 1). Similarly, seven ligands (2-amino octadecane-1, 3, 4-triol, carvacrol, carvone, 14-octacosanol, 9, 10-pinanediol, pinene-9, 10-diol, 4-(3-hydroxypropyl)-2-methoxyphenyl and 3-[4-hydroxypheny l]-2-propen-1-ol]) of U. dioica (Stinging nettle) have predicted to shown skin sensitization effect.
The docking analysis showed that afzelin exhibited the maximum binding energy (-7.2 kcal/mol) with the human carbonic anhydrase II (hCA-II) enzyme. In contrast, 14-octacosanol exhibited the least binding energy (-4.1 kcal/mol) with the hCA-II enzyme (Table 2). The binding energy analysis of the present study showed the hCA-II in the following order: afzelin (-7.2 kcal/mol), ˂ estra-1,3,5(10)-trien-17B-ol, ethyl iso- allocholate, pinoresinol (-7.1 kcal/mol), ˂ astragalin (-6.9 kcal/mol), ˂ neoolivil, stigmastane-3, 6-diol (-6.7 kcal/mol), ˂ cycloolivil, kephton, 5,6,7,8-tetrahydroxy-2-(4-hydroxyphenyl)chroman-4-one (-6.6 kcal/mol), ˂ 1-[3,4-dihydroxyphenyl]-1,2-propanediol (-6.4 kcal/mol), ˂ scoparone (-6.0 kcal/mol), ˂ carvone (-5.8 kcal/mol), ˂ oxime- methoxy-phenyl (-5.7 kcal/mol), ˂ 3-[4- hydroxypheny l]-2-propen-1-ol, 3- hydroxyacetophenone (-5.6 kcal/mol), ˂ 9, 10-pinanediol (-5.5 kcal/mol), ˂ 4-(3-hydroxypropyl)-2-methoxyphenol (-5.4 kcal/mol), ˂ pinene-9,10- diol (-5.2 kcal/mol), ˂ 2-amino Octadecane-1,3,4-triol (-5.1 kcal/mol), ˂ 6,6-dimethyl-2-methylene (-4.8 kcal/mol), ˂ 1,2,3-butanetriol (-4.4 kcal/mol) and ˂ 14-octacosanol (-4.1 kcal/mol). Similarly, docking analysis revealed that stigmastane-3, 6-diol exhibited the maximum binding energy (-9.5 kcal/mol) with the human 11 beta-hydroxysteroid dehydrogenases type 1 (h11 beta-HSD1) enzyme. In contrast, 1, 2, and 3-butanetriol exhibited the least binding energy (-4.3 kcal/mol) with the h11 beta-HSD1 enzyme (Table 2). The binding energy analysis of the current study showed the h11 beta-HSD1 enzyme in the following order: stigmastane-3, 6-diol (-9.5 kcal/mol), ˂ ethyl iso- allocholate (-9.3 kcal/mol), ˂ estra-1,3,5(10)-trien-17B-ol (-9.1 kcal/mol), ˂ afzelin, astragalin (-9.0 kcal/mol), ˂ pinoresinol (-8.5 kcal/mol), ˂ kephton, neoolivil (-8.1 kcal/mol), ˂ 5,6,7,8-tetrahydroxy-2-(4-hydroxyphenyl)chroman-4-one (-8.0 kcal/mol), ˂ cycloolivil (-7.2 kcal/mol), ˂ scoparone (-6.3 kcal/mol), ˂ 1-[3,4-dihydroxyphenyl]-1,2-propanediol (-6.1 kcal/mol), ˂2-Amino Octadecane-1,3,4-triol, carvacrol, 14-octacosanol (-5.7 kcal/mol), ˂ carvone, pinene-9,10- diol, 4-(3-hydroxypropyl)-2-methoxyphenol, 3-[4- hydroxypheny l]-2-propen-1-ol (5.6 kcal/mol), ˂ 3- hydroxyacetophenone (-5.4 kcal/mol), ˂ 6,6-dimethyl-2-methylene (-5.2 kcal/mol) and ˂ 1,2,3-butanetriol (-4.3 kcal/mol).
Table 2. The binding energy analysis of 24 selected Urtica dioica (Stinging nettle) ligands with the human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11 beta-HSD1) and human dual specificity phosphatase (hCDC25B) enzyme using the Webina docking method.
| Ligand name | hCA-II | h11 beta-HSD1 | hCDC25B |
| Binding energy (-kcal/mol) | |||
| Afzelin | -7.2 | -9 | -8.1 |
| 2-Amino Octadecane-1,3,4-triol | -5.1 | -5.7 | -7.9 |
| Astragalin | -6.9 | -9 | -8.5 |
| 1,2,3-Butanetriol | -4.4 | -4.3 | -5.6 |
| Carvacrol | -5.6 | -5.7 | -6.3 |
| Carvone | -5.8 | -5.6 | -6.3 |
| Cycloolivil | -6.6 | -7.2 | -7.3 |
| Estra-1,3,5(10)-trien-17B-ol | -7.1 | -9.1 | -7.0 |
| Ethyl iso- allocholate | -7.1 | -9.3 | -7.1 |
| Kephton | -6.6 | -8.1 | -8.2 |
| Neoolivil | -6.7 | -8.1 | -8.1 |
| 14-Octacosanol | -4.1 | -5.7 | -7.6 |
| Oxime- methoxy-phenyl | -5.7 | -5.2 | -6.4 |
| 9, 10-Pinanediol | -5.5 | -5.2 | -6.3 |
| Pinene-9,10- diol | -5.2 | -5.6 | -6.4 |
| Pinoresinol | -7.1 | -8.5 | -7.2 |
| Scoparone | -6 | -6.3 | -6.4 |
| 6,6-dimethyl-2-methylene | -4.8 | -5.2 | -6.1 |
| 1-[3,4-Dihydroxyphenyl]-1,2-propanediol | -6.4 | -6.1 | -6.2 |
| 4-(3-hydroxypropyl)-2- methoxyphenol | -5.4 | -5.6 | -6.6 |
| 3-[4- Hydroxypheny l]-2-propen-1-ol | -5.6 | -5.6 | -6.4 |
| 3- Hydroxyacetophenone | -5.6 | -5.4 | -6.3 |
| Stigmastane-3, 6-diol | -6.7 | -9.5 | -7.6 |
| 5,6,7,8-tetrahydroxy-2-(4- hydroxyphenyl)chroman-4-one | -6.6 | -8 | -6.8 |
Furthermore, docking analysis revealed that astragalin exhibited the highest binding energy (-8.5 kcal/mol) with the human dual specificity phosphatase (hCDC25B) enzyme. In contrast, 1, 2, and 3-butanetriol showed the least binding energy (-5.6 kcal/mol) with the hCDC25B (Table 2). The binding energy analysis of the present study showed the hCDC25B enzyme in following order: astragalin (-8.5 kcal/mol), ˂ kephton (-8.2 kcal/mol), ˂ afzelin, neoolivil (-8.1 kcal/mol), ˂ 2-amino octadecane-1,3,4-triol (-7.9 kcal/mol), ˂ 14-octacosanol, stigmastane-3, 6-diol (-7.6 kcal/mol), ˂ cycloolivil (-7.3 kcal/mol), ˂ pinoresinol (-7.2 kcal/mol), ˂ 5,6,7,8-tetrahydroxy-2-(4-hydroxyphenyl)chroman-4-one (-6.8 kcal/mol), ˂ 4-(3-hydroxypropyl)-2- methoxyphenol (-6.6 kcal/mol), ˂ oxime- methoxy-phenyl, pinene-9,10- diol, scoparone, 3-[4- hydroxypheny l]-2-propen-1-ol (-6.4 kcal/mol),˂ carvacrol, carvone, 9, 10-pinanediol, 3- hydroxyacetophenone (-6.3 kcal/mol), ˂ 1-[3,4-dihydroxyphenyl]-1,2-propanediol (-6.2 kcal/mol), ˂ 6,6-dimethyl-2-methylene (-6.1 kcal/mol) and ˂ 1,2,3-Butanetriol (-5.6 kcal/mol).
Discussion
The phyto-constituents from U. dioica (Stinging nettle) have been reported by employing traditional liquid chromatography (LC) separation, high-performance liquid chromatography [16] and ultra-performance liquid chromatography (UPLC) techniques. Moreover, LC-MS [17] and LC-ESI-MS [18] have been used for isolation and chemical characterization. Furthermore, gas chromatography (GC), liquid chromatography (LC) along with mass spectrometry (MS) analytical techniques have been applied for chemical characterization [19]. Numerous reports have demonstrated that U. dioica (Stinging nettle) extracts have shown to possess several biological properties such as analgesic, anti-diabetic, anti-cancer, anti-inflammatory, anti-microbial, anti-mutagenic, antioxidant, anti-ulcer, cardiovascular, immune-modulatory activities [20, 21]. U. dioica (Stinging nettle) has been known for food applications and has been consumed as green salad, soup, and tea. Chlorophyll extracted on a large scale has been used as a food coloring (green) agent [22]. Figure 1 shows the U. dioica (Stinging nettle) plant image. The current study findings are based on in silico analysis which provides detailed information about these 24 ligands of U. dioica (Stinging nettle) as hCA-II, h11beta-HSD1, and hCDC25B enzyme inhibition activities and are considered as initial research work. Furthermore, in vitro and in vivo experiments are required to confirm these 24 phytoconstituents of U. dioica (Stinging nettle) as good enzyme inhibitors against hCA-II, h11beta-HSD1, and hCDC25B activities.
Figure 1. U. dioica (Stinging nettle) plant.
Represents the Urtica dioica (Stinging nettle) plant photo taken from Kollar Village, Villupuram District, Tamil Nadu, India, on January 13, 2021.
Moreover, Durak et al. reported that the U. dioica aqueous extract has been shown to inhibit adenosine deaminase (ADA) activity [23]. Roschek et al. reported that the U. dioica aqueous ethanolic extract has shown to inhibit (i) mast cell tryptase, (ii) cyclooxygenases (COX 1 and 2), and (iii) hematopoietic prostaglandin D2 synthase (HPGDS); in addition, it reported to possess both the histamine receptor antagonist and histamine receptor negative agonist activities [5]. Altamimi et al. reported that the U. dioica aqueous ethanolic extract has been shown to inhibit (i) maltase, (ii) sucrase, (iii) lactase, and as well as glucose transport inhibitory activities [24]. Thus, in the current investigation, we have chosen the human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11 beta-HSD1), and human dual specificity phosphatase (hCDC25B) as the target enzymes. Before carrying out the docking studies, it is important to know the toxicity nature of chosen U. dioica (Stinging nettle) ligands in order to avoid drug failure as well as to reduce drug development costs [13].
According to International Regulatory Guidelines (namely ICH S7B) all new drugs under the drug development (DD) process should be assessed for effects on the human ether-a-go-go-related gene (hERG) channel prior to clinical trials [25]. In the current investigation, six ligands (afzelin, cycloolivil, estra-1,3,5(10)-trien-17B-ol, kephton, 14-octacosanol and stigmastane-3, 6-diol) of U. dioica (Stinging nettle) have predicted to exhibit hERG II inhibition activity, thus six ligands have failed to obey with the above said regulatory guideline (ICH S7B). Gansser and Spiteller (1995) reported for the first time the presence of 14-octacosanol from U. dioica (Stinging nettle) root extract and shown to have weak aromatase inhibition activity [26]. Mares and colleagues have reported that inhibitors of human carbonic anhydrase II (hCA-II) have been used for treating glaucoma, neoplasms, and neurodegenerative diseases [27]. The current investigation showed that all 24 ligands of U. dioica (Stinging nettle) have docked successfully with the human carbonic anhydrase II (hCA-II) enzyme, which was in good agreement with a recent report [28]. Figure 2 shows the docking image, where the afzelin ligand docked with the human dual specificity phosphatase (hCDC25B).
Figure 2. The docking image where afzelin ligand docked with the human dual specificity phosphatase (hCDC25B).
Hughes et al. reported that inhibitors of human 11 beta-hydroxysteroid dehydrogenases type 1 (h11 beta-HSD1) have been used for treating atherosclerosis, type 2 diabetes mellitus (DM), and metabolic syndrome including obesity [29]. Li et al. reported that inhibitors of human dual specificity phosphatases (DUSP) emerging as a new target in the field of kidney/renal disease [30].
Limitations and future recommendations
The current study findings are based on in silico analysis which provides detailed information about these 24 ligands of U. dioica (Stinging nettle) as hCA-II, h11beta-HSD1, and hCDC25B enzyme inhibition activities and are considered initial research work. Furthermore, in vitro and in vivo experiments are required to confirm these 24 phytoconstituents of U. dioica (Stinging nettle) as good enzyme inhibitors against hCA-II, h11beta-HSD1, and hCDC25B activities.
Conclusions
The present study showed that all 24 ligands of U. dioica (Stinging nettle) have dock effectively with the three target enzymes namely human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11beta-HSD1) and human dual specificity phosphatase (hCDC25B). Interestingly, 1, 2, and 3-butanetriol showed the least binding energy (-4.3 and -5.6 kcal/mol) with both the h11 beta-HSD1 and hCDC25B enzymes, respectively. Thus, the results of the present investigation have shown good knowledge of these 24 ligands of U. dioica (Stinging nettle) as potential suppressers against hCA-II, h11beta-HSD1, and hCDC25B concerning the treatments of atherosclerosis, glaucoma, metabolic syndrome (including obesity), neoplasms, neurodegenerative diseases, renal disease, and type 2 DM.
The authors have declared that no competing interests exist.
Author Contributions
Concept and design: Radhakrishnan Narayanaswamy, Angel Jenifer Arulselvan, Mani Sankar Manimuthu
Acquisition, analysis, or interpretation of data: Radhakrishnan Narayanaswamy, Angel Jenifer Arulselvan, Mani Sankar Manimuthu
Drafting of the manuscript: Radhakrishnan Narayanaswamy, Angel Jenifer Arulselvan, Mani Sankar Manimuthu
Critical review of the manuscript for important intellectual content: Radhakrishnan Narayanaswamy, Mani Sankar Manimuthu
Supervision: Radhakrishnan Narayanaswamy
Human Ethics
Consent was obtained or waived by all participants in this study
Animal Ethics
Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.
References
- 1.Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Supuran CT. Nat Rev Drug Discov. 2008;7:168–181. doi: 10.1038/nrd2467. [DOI] [PubMed] [Google Scholar]
- 2.11β-Hydroxysteroid dehydrogenase type 1(11β-HSD1) mediates insulin resistance through JNK activation in adipocytes. Peng K, Pan Y, Li J, et al. Sci Rep. 2016;6:37160. doi: 10.1038/srep37160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Dual-specificity phosphatase CDC25B was inhibited by natural product HB-21 through covalently binding to the active site. Zhang S, Jia Q, Gao Q, Fan X, Weng Y, Su Z. Front Chem. 2018;6:531. doi: 10.3389/fchem.2018.00531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Urtica spp.: ordinary plants with extraordinary properties. Kregiel D, Pawlikowska E, Antolak H. Molecules. 2018;23:1664. doi: 10.3390/molecules23071664. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nettle extract (Urtica dioica) affects key receptors and enzymes associated with allergic rhinitis. Roschek B Jr, Fink RC, McMichael M, Alberte RS. Phytother Res. 2009;23:920–926. doi: 10.1002/ptr.2763. [DOI] [PubMed] [Google Scholar]
- 6.Urtica dioica-derived phytochemicals for pharmacological and therapeutic applications. Taheri Y, Quispe C, Herrera-Bravo J, et al. Evid Based Complement Alternat Med. 2022;2022:4024331. doi: 10.1155/2022/4024331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Randomized controlled trial of nettle sting for treatment of base-of-thumb pain. Randall C, Randall H, Dobbs F, Hutton C, Sanders H. J R Soc Med. 2000;93:305–309. doi: 10.1177/014107680009300607. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Long-term efficacy and safety of a combination of sabal and urtica extract for lower urinary tract symptoms--a placebo-controlled, double-blind, multicenter trial. Lopatkin N, Sivkov A, Walther C, et al. World J Urol. 2005;23:139–146. doi: 10.1007/s00345-005-0501-9. [DOI] [PubMed] [Google Scholar]
- 9.Combined Sabal and Urtica extract compared with finasteride in men with benign prostatic hyperplasia: analysis of prostate volume and therapeutic outcome. Sökeland J, Albrecht J. Urologe A. 1997;36:327–333. doi: 10.1046/j.1464-410x.2000.00776.x. [DOI] [PubMed] [Google Scholar]
- 10.Randomized, double-blind study of freeze-dried Urtica dioica in the treatment of allergic rhinitis. Mittman P. Planta Med. 1990;56:44–47. doi: 10.1055/s-2006-960881. [DOI] [PubMed] [Google Scholar]
- 11.Antihyperglycemic and antihyperlipidemic activity of Urtica dioica on type 2 diabetic model rats. Das M, Sarma BP, Rokeya B, et al. http://journals.lww.com/jodb/abstract/2011/02020/a_ntihyperglycemic_and_antihyperlipidemic_activity.2.aspx J Diabetol. 2011;2:2. [Google Scholar]
- 12.Pharmacognostical review of Urtica dioica L. Joshi BC, Mukhija M, Kalia AN. http://www.greenpharmacy.info/index.php/ijgp/article/view/414 Int J Green Pharm. 2014;8:201–209. [Google Scholar]
- 13.Stitch, physicochemical, ADMET, and in silico analysis of selected Mikania constituents as anti-inflammatory agents. Radhakrishnan N, Prabhakaran VS, Wadaan MA, et al. Processes. 2023;11:1722. [Google Scholar]
- 14.Molecular docking analysis of organic acids (OA) from honey as modulators of human ferritin, transferrin, and hepcidin. Kumaraswamy S, Arumugam G, Pandurangan AK, et al. J Microbiol Biotech Food Sci. 2023;12:5743. [Google Scholar]
- 15.Webina: an open-source library and web app that runs AutoDock Vina entirely in the web browser. Kochnev Y, Hellemann E, Cassidy KC, Durrant JD. Bioinformatics. 2020;36:4513–4515. doi: 10.1093/bioinformatics/btaa579. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Extraction and HPLC analysis of phenolic compounds in leaves, stalks, and textile fibers of Urtica dioica L. Pinelli P, Ieri F, Vignolini P, Bacci L, Baronti S, Romani A. J Agric Food Chem. 2008;56:9127–9132. doi: 10.1021/jf801552d. [DOI] [PubMed] [Google Scholar]
- 17.LC-PDA-MS-profiles of phenolic compounds in extracts of aerial parts of Urtica species. Bucar F, Britzmann B, Streit B, et al. Planta Med. 2006;72:152. [Google Scholar]
- 18.Determination of phytochemical content by LC-MS/MS, investigation of antioxidant capacity, and enzyme inhibition effects of nettle (Urtica dioica) Uğur Y, Güzel A. Eur Rev Med Pharmacol Sci. 2023;27:1793–1800. doi: 10.26355/eurrev_202303_31540. [DOI] [PubMed] [Google Scholar]
- 19.Medicinal plant genus Urtica traditional uses phytochemical and pharmacological review. Hussain M. Int J Sci Eng Res. 2019;10:557–607. [Google Scholar]
- 20.Urtica dioica (stinging nettle): a review of its chemical, pharmacological, toxicological and ethnomedical properties. Seliya M, Kothiyal P. http://www.pharmascholars.com/articles/urtica-dioica-stinging-nettle-a-review-of-its-chemical-pharmacological-toxicological-and-ethnomedical-properties.pdf Int J Pharm. 2014;4:270–277. [Google Scholar]
- 21.Dietary plants for the prevention and management of kidney stones: preclinical and clinical evidence and molecular mechanisms. Nirumand MC, Hajialyani M, Rahimi R, Farzaei MH, Zingue S, Nabavi SM, Bishayee A. Int J Mol Sci. 2018;19:765. doi: 10.3390/ijms19030765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Bioactive compounds in wild nettle (Urtica dioica L.) leaves and stalks: polyphenols and pigments upon seasonal and habitat variations. Repajić M, Cegledi E, Zorić Z, et al. Foods. 2021;10:190. doi: 10.3390/foods10010190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Aqueous extract of Urtica dioica makes significant inhibition on adenosine deaminase activity in prostate tissue from patients with prostate cancer. Durak I, Biri H, Devrim E, Sözen S, Avci A. Cancer Biol Ther. 2004;3:855–857. doi: 10.4161/cbt.3.9.1038. [DOI] [PubMed] [Google Scholar]
- 24.Hydroethanolic extract of Urtica dioica L. (stinging nettle) leaves as disaccharidase inhibitor and glucose transport in Caco-2 hinderer. Altamimi MA, Abu-Reidah IM, Altamimi A, Jaradat N. Molecules. 2022;27:8872. doi: 10.3390/molecules27248872. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Inhibition of HERG potassium channels by celecoxib and its mechanism. Frolov RV, Ignatova II, Singh S. PLoS One. 2011;6:0. doi: 10.1371/journal.pone.0026344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Aromatase inhibitors from Urtica dioica roots. Gansser D, Spiteller G. Planta Med. 1995;61:138–140. doi: 10.1055/s-2006-958033. [DOI] [PubMed] [Google Scholar]
- 27.Bioinformatics tools for the analysis of active compounds identified in Ranunculaceae species. Mareş C, Udrea AM, Şuţan NA, Avram S. Pharmaceuticals (Basel) 2023;16:842. doi: 10.3390/ph16060842. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.In silico analysis of selected nutrition rich fruit of Bunch berry (Lantana camara) constituents as human acetylcholinesterase (hAchE), carbonic anhydrase II (hCA-II) and carboxylesterase 1 (hCES-1) inhibitory agents. Prakash VS, Radhakrishnan N, Vasantha-Srinivasan P, Veeramani C, El Newehy AS, Alsaif MA, Al-Numair KS. Saudi J Biol Sci. 2023;30:103847. doi: 10.1016/j.sjbs.2023.103847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.11-Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors in type 2 diabetes mellitus and obesity. Hughes KA, Webster SP, Walker BR. Expert Opin Investig Drugs. 2008;17:481–496. doi: 10.1517/13543784.17.4.481. [DOI] [PubMed] [Google Scholar]
- 30.Dual-specificity phosphatases and kidney diseases. Li H, Xiong J, Du Y, Huang Y, Zhao J. Kidney Dis (Basel) 2022;8:13–25. doi: 10.1159/000520142. [DOI] [PMC free article] [PubMed] [Google Scholar]