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Article

GC/MS Profiling, In Vitro Antidiabetic Efficacy of Origanum compactum Benth. Essential Oil and In Silico Molecular Docking of Its Major Bioactive Compounds

by
Hamza Assaggaf
1,
Naoufal El Hachlafi
2,*,
Mohamed El fadili
3,
Amine Elbouzidi
4,
Hayat Ouassou
5,
Mohamed Jeddi
2,
Sulaiman Mohammed Alnasser
6,
Ahmed Qasem
1,
Ammar Attar
1,
Ammar AL-Farga
7,*,
Othman A. Alghamdi
7,
Elsayed Eldeeb Mehana
8 and
Hanae Naceiri Mrabti
9
1
Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah 21955, Saudi Arabia
2
Laboratory of Microbial Biotechnology and Bioactive Molecules, Faculty of Sciences and Technologies, Sidi Mohamed Ben Abdellah University, Imouzzer Road, Fez 30000, Morocco
3
LIMAS Laboratory, Faculty of Sciences Dhar El Mehraz, Sidi Mohammed Ben Abdellah University, BP 1796 Atlas, Fez 30000, Morocco
4
Laboratoire d’Amélioration des Productions Agricoles, Biotechnologie et Environnement (LA-PABE), Faculté des Sciences, Université Mohammed Premier, Oujda 60000, Morocco
5
Higher Institute of Nursing Professions and Health Techniques, Oujda 60000, Morocco
6
Department of Pharmacology and Toxicology, Unaizah College of Pharmacy, Qassim University, Buraidah 51452, Saudi Arabia
7
Department Biological Sciences, College of Science, University of Jeddah, Jeddah 80203, Saudi Arabia
8
Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Alexandria 5424041, Egypt
9
Center of Data Science and Sustainable Technologies, INTI International University, Nilai 71800, Malaysia
*
Authors to whom correspondence should be addressed.
Catalysts 2023, 13(11), 1429; https://doi.org/10.3390/catal13111429
Submission received: 10 September 2023 / Revised: 4 November 2023 / Accepted: 10 November 2023 / Published: 13 November 2023
(This article belongs to the Section Biocatalysis)
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Abstract

:
Diabetes is a global health concern with significant implications for individuals and healthcare systems. Finding effective and safe antidiabetic agents is crucial for the management of this chronic disease. Natural products have emerged as potential alternatives to allopathic drugs, offering a vast source of bioactive compounds. In this study, we conducted an assessment of the antidiabetic potential of Origanum compactum essential oil, employing a two-pronged approach, i.e., experimental investigation and computational docking analysis. The results of gas chromatography–mass spectrometry (GC-MS) showed that thymol (54.6%), carvacrol (23.18%), and p-cymene (7.12%) were the major compounds. Experimental assessments revealed higher IC50 values (150 µg/mL for α-amylase; 120 µg/mL for α-glucosidase) of O. compactum oil, compared to the control drug acarbose. In silico analysis revealed the best binding affinity of the oil components (carvacrol and thymol) with human NADPH oxidase, while the lysosomal acid-α-glucosidase and salivary amylase also demonstrated good binding affinity towards carvacrol and thymol. Our findings highlight the translational potential of O. compactum oil-based treatment for diabetes mellitus and provide a basis for further studies on the modulation of NADPH oxidase, amylase inhibition, and α-glucosidase by antidiabetic natural products. However, further in vivo investigations are strongly required to confirm the results of in vitro antidiabetic effect of O. compactum EO.

Graphical Abstract

1. Introduction

Diabetes is a prevalent and rapidly growing health condition worldwide, characterized by elevated blood glucose levels [1]. According to global statistics, the prevalence of diabetes has reached alarming levels, affecting millions of individuals across all age groups and socio-economic backgrounds [2]. This long-lasting illness carries important consequences for the well-being of the public, healthcare systems, and the overall quality of life for those affected. Its effects span the physical realm, as it raises the likelihood of experiencing serious complications like heart problems, impaired kidney function, nerve damage, and vision loss [3]. Finding effective and safe treatments for this disease is incredibly important in order to manage and control it. Common treatments include lifestyle modifications, oral medications, and insulin therapy [4,5]. Due to the commonly associated side effects of conventional treatments, there has been a growing interest in natural products as alternative options for diabetes treatment [6,7,8]. These are a colossal source of bioactive compounds, having therapeutic effects. In addition, natural products have a long history of traditional use and often exhibit fewer side effects. In the context of diabetes, natural products hold promise due to their potential to modulate glucose metabolism, enhance insulin sensitivity, protect pancreatic beta cells, and mitigate diabetic complications. Joshi et al. have reviewed the potential of berberine, quercetin, etc. for targeting the 5′-adenosine monophosphate-activated protein kinase (MAPK) pathway and management of diabetes [9]. Cymbopogon jwarancusa, an aromatic grass, has also exhibited antiglycemic effect in a rat model [10]. Trans-tiliroside from Potentilla chinesis has been reported to heal pancreatic tissue in diabetic rats [11]. Heghes et al. have reviewed the potential of oil-bearing plants, i.e., Mentha x piperita L., Melissa officinalis L., Cuminum cyminum L., or Pistacia lentiscus L. var. chia, in managing diabetes [12].
Modulation of α-amylase and α-glucosidase, the enzymes responsible for breaking down starch in the intestines, can be used to manage high blood sugar levels. Currently, acarbose, miglitol, and voglibose are the approved inhibitors for these enzymes [13]. However, the use of these inhibitors is impeded by gastrointestinal side effects, despite their ability to slow down glucose absorption [14]. Therefore, the development of efficacious and safe antidiabetic agents against the key enzymes, i.e., α-amylase and α-glucosidase, is highly desired. Exploring the potential of natural products and their essential oils (EOs) as alternative treatments for diabetes represents an exciting avenue in drug discovery and development. Eid et al. have reported a very good antiα-amylase activity of Ocimum basilicum seed EO, compared to the control acarbose [15]. EO from an ornamental plant from Egypt, Myrtus communis L. [16], and an evergreen Himalayan tree cone, Cedrus deodara [17], has also demonstrated good α-amylase activity. EO components of rosemary have also been reported to have antiglycemic effects [18]. A study by Capetti et al. has reported the metabolites from Eos of Myristica fragrans, Eucalyptus radiata, and Laurus nobilis to have antiglycemic effects equivalent to that of acarbose [19]. Daoudi et al. demonstrated that the inhibition activity of roasted Argania spinosa L. seed oils was higher against α-amylase and α-glucosidase compared to the unroasted seed oil. However, unroasted seed oil showed better antiglycemic activity against diabetic rat models compared to roasted seed oil [20].
O. compactum, commonly known as compact oregano, is an aromatic plant from Morocco (local name: Zaatar), that has been traditionally used for its medicinal properties [21]. Among the numerous other benefits, its oil has emerged as a promising candidate for antidiabetic therapy [22]. Preliminary studies have indicated that the oil also exhibits antioxidant activity in different biological systems [23]. Recent investigations have shown that O. compactum EOs possess promising health benefits and biological properties, including antioxidant, anticancer, insecticidal, and anti-inflammatory activities. Moreover, O. compactum EOs have also been found to exhibit interesting antimicrobial effects against yeast, molds, and Gram-positive and Gram-negative bacteria [21]. El Abdali et al. [24] have already demonstrated the antimicrobial and antioxidant potential of O. compactum EOs through in vitro and in silico approaches. However, there is no published work about the antidiabetic properties of this oil. Indeed, this exploratory investigation is the first to determine the antidiabetic activity of this oil through in vitro and in silico analysis.
The unique bioactive compounds present in O. compactum oil make it an intriguing subject for further investigation, particularly regarding its antidiabetic mechanisms and potential therapeutic applications. O. compactum oil is generally rich in oxygenated monoterpenes such as thymol and carvacrol, which are known by their broad bioactivities [25,26,27]. They possess valuable antimicrobial, antioxidant, antidiabetic, anti-inflammatory, anticancer, and insecticidal activities [28,29].
Here, we utilized the EO of O. compactum for antienzymatic activity analysis (against α-amylase and α-glucosidase). In addition, we performed in silico analysis to find the essential residues of these enzymes involved in inhibition. We also utilized a docking approach to study the components of the oil binding with antioxidant NADPH oxidase to analyze the antioxidant activity at a fundamental level. Molecular docking is a useful in silico method employed for binding studies [30,31]. Molecular docking predicts the binding modes and affinities of compounds with target proteins, providing insights into their potential interactions and affinity [32]. It is a cost-effective and time-efficient approach to study binding [33]. Hence, we elucidated how the key components of the O. compactum oil exerted their antidiabetic effects. This work aims to provide valuable insights into the potential therapeutic benefits of O. compactum oil and its mechanisms of action against diabetes by analyzing the binding interactions. These findings can guide future studies and contribute to the development of safe and novel antidiabetic agents.

2. Results and Discussion

2.1. Chemical Composition

The identification of volatile components from O. compactum was performed using GC-MS analysis. The results are given in Table 1, which summarizes the chemical structure, molecular formula, Kovats index, and relative peak area of each component. A total of 10 components, accounting for 97.65% of the total peak area, were detected. Indeed, O. compactum EO was mainly represented by oxygenated monoterpenes (80.7%), while monoterpene hydrocarbons (8.24%), oxygenated sesquiterpenes (5.34%), and sesquiterpene hydrocarbons (3.37%) were revealed in the lowest percentages. The major identified components were thymol (54.6%), carvacrol (23.18%), and p-cymene (7.12%). Moreover, molecules such as caryophyllene oxide (5.34%), β-caryophyllene (3.37%), and linalool (2.64%) were also noticed in modest amounts.
These findings are in accordance with those indicated by numerous investigations. In fact, a recent exploration carried out by Hayani et al. [34] showed that the EO from O. compactum of the Ouazzane region (Morocco) was particularly rich in oxygenated monoterpene (60.9%) compounds, including thymol (38.59%) and carvacrol (26.65%). In addition, similar results were obtained by Bouyahya and his colleagues, who demonstrated the abundance of the isomeric oxygenated monoterpenes carvacrol (24.71%) and thymol (15.32%) [26]. Additionally, Ouedrhiri et al. [35] indicated that oregano oil was rich in carvacrol (47.81%), γ-terpinene (17.25%), and thymol (15.70%). As evidenced in several works, carvacrol and thymol as well as their biosynthetic precursors, such as cymene and γ-terpinene, represent a major part of total oil components (more than 70%) [34,36,37]. Moreover, β-caryophyllene and caryophyllene oxide were also observed in significant amounts [25,38,39]. Therefore, the chemical composition may be related to biosynthetic pathways, promoting the overexpression of some components and blocking the synthesis of others [40,41].
On the other hand, it has been shown that Origanum species have substantial chemical variability in their volatile components, which could be explained by several factors, including plant origin, season and climatic conditions, soil constituents, precipitation, phenological stage, and drying process and also could be genetically determined [34,38,42,43]. Interestingly, the abundance of thymol and carvacrol in O. compactum oil, as known biologically active components, has made this oil a valuable source for development of novel pharmaceutical agents.

2.2. Antidiabetic Activity

One of the most widely used approaches to decrease the postprandial hyperglycemia (PPHG) in diabetes mellitus is by lowering the absorption of postprandial serum glucose levels via the inhibition of carbohydrate-hydrolyzing enzymes such as α-glucosidase and α-amylase [44,45]. In order to discover new and safer alternative compounds for diabetes mellitus, it is crucial to assess the antidiabetic properties of medicinal plants and their bioactive components. In the present study, EO of O. compactum was assessed for its inhibitory effect on α-amylase and α-glucosidase enzymes by an in vitro method. Our results show that O. compactum EO demonstrated an important ability to inhibit in vitro pancreatic α-amylase and α-glucosidase (Table 2). In the α-amylase inhibition assay, the EOs exhibited an interesting inhibitory effect on α-amylase activity with an IC50 value of 150.11 µg/mL. In the α-glucosidase inhibition assay, the studied EO has promising enzyme inhibitory activity against α-glucosidase with an IC50 value of 119.84 µg/mL. Acarbose was used as a standard reference drug, which showed α-amylase inhibitory activity with an IC50 value of 98.24 µg/mL and α-glucosidase inhibitory activity with an IC50 value of 62.31 µg/mL. From our results, EOs obtained from O. compactum have been shown to possess antidiabetic activity against the three selected enzymes. Furthermore, previous studies have reported that Origanum species from Tunisia exhibited stronger inhibitory activities against pancreatic α-amylase with a percentage of 90, 80, and 75%, respectively [46]. On the other hand, it has been reported that Origanum species from Turkey exhibit a potent inhibitory effect against α-amylase (0.13 mmol acarbose equivalent/g oil and 0.14 mmol acarbose equivalent/g oil) and α-glucosidase activity (6.04 mmol acarbose equivalent/g oil and 0.88 mmol acarbose equivalent/g oil) [47]. The antidiabetic activity of the EOs may be related to several bioactive compounds. Numerous studies have shown antidiabetic properties of thymol and carvacrol by in vitro or in vivo assays [48]. To our knowledge, this study is the first to report the α-amylase and α-glucosidase inhibitory activity of O. compactum EOs, suggesting their potential application as novel and effective sources of antidiabetic agents for the treatment of diabetes mellitus.

2.3. ADME and Toxicity Prediction

The use of computational drug-likeness assessments, conducted in silico, plays a crucial role in expediting the drug discovery process by effectively filtering and prioritizing potential candidates [29,49]. These computer-based methods not only save time and resources but also reduce the experimental workload, enabling the early identification of molecules with favorable pharmacokinetic properties and target interactions [50]. In order to adhere to Lipinski’s rule of five, specific physical and chemical characteristics are required, including having fewer than 5 hydrogen bond donors, fewer than 10 hydrogen bond acceptors, no more than 10 nitrogen or oxygen atoms, a molecular weight below 500 Da, and a MLOGP value less than or equal to 4.15 [51]. Notably, all the phytoconstituents satisfy Lipinski’s rule of five (Table 3). Furthermore, the analysis of the ADME–toxicity profile provides further confirmation of the favorable characteristics of the small molecules under investigation. Firstly, all four small molecules exhibit a high level of predicted human intestinal absorption (HIA) exceeding 93%, indicating their potential to be well-absorbed in the human digestive system. Moreover, the assessment of their blood–brain barrier (BBB) permeability and central nervous system (CNS) permeabilities yields promising results, with all four small molecules demonstrating values exceeding −1 Log BB, falling within the range of −1 to −3 Log PS. These findings suggest that these compounds possess the ability to pass through the BBB and access the central nervous system, which is a crucial attribute for drugs targeting neurological conditions. Additionally, the metabolism test reveals specific interactions of the compounds with cytochrome enzymes. The C2 compound is predicted to be an inhibitor of cytochromes 1A2, 2C9, and 2C19, suggesting its potential to interfere with the metabolism of substances processed by these enzymes. On the other hand, C3 and C4 are predicted to be inhibitors of cytochrome 1A2, indicating their potential impact on the metabolic pathways involving this particular enzyme.
The forecast of physicochemical characteristics provides validation that thymol, carvacrol, p-cymene, and caryophyllene oxide adhere to Lipinski’s five rules (MW ≤ 500 g/mol, 40 ≤ MR ≤ 130, HBD < 5, Log P (octanol/water) < 5, and HBA ≤ 10) as depicted in Table 3 [29,49]. Furthermore, the ADME–toxicity profile examination verifies that the four volatile components were forecasted to exhibit favorable human intestinal absorption (HIA), surpassing 93%. Additionally, these components were projected to have blood–brain barrier (BBB) and central nervous system (CNS) permeabilities greater than −1 Log BB, falling within the range of −1 to −3 Log PS. The metabolism test declares that the C2 compound was predicted as an inhibitor of 1A2, 2C9, and 2C19 cytochromes, while C3 and C4 were predicted as inhibitors of 1A2 cytochrome [50].
The AMES toxicity test confirms that the four chemical compounds were predicted to not have toxicity in the human body, and none of these compounds showed a hepatotoxic effect, but they all present a positive skin sensitization, as listed in Table 4 [52]. The BOILED-Egg predictive model, primarily used for bioactive compounds, indicates that every chemical compound belongs to the yellow Egan egg category, leaving no exceptions. This suggests that they are anticipated to passively traverse the blood–brain barrier (BBB) [29,49]. Consequently, they are predicted to be agents affecting the central nervous system (CNS) with the highest likelihood of crossing the BBB (Figure 1) [53]. The assessment of bioavailability indicates that all the compounds fall within the favorable range for oral bioavailability, as evident by their consistent placement within the pink zone on the bioavailability radar (as depicted in Figure 2). This positioning unequivocally categorizes them as drug-like substances, with no exceptions.

2.4. Molecular Docking

Two- and three-dimensional visualizations of intermolecular interactions shown in Figure 3 confirm that carvacrol (C2) and thymol (C3), as major compounds of the studied plant, were docked to antioxidant protein. Initially, C2 and C3 compounds were docked in the active sites of NADPH oxidase protein encoded as 2CDU.pdb with binding energies of −6.26 Kcal/mol and −5.83 Kcal/mol, respectively. Both compounds share a number of common intermolecular interactions such as the pi–sigma bond type with His10 amino acid and two hydrogen bonds with Leu299 and Asp282 amino acid residues. In addition, there are alkyl and pi–alkyl bonds with Ala11, Ala300, and Ala303 amino acid residues.
Thereafter, the candidate ligands were docked to antidiabetic protein of human salivary amylase (PDB ID:1SMD) as shown in Figure 4. The compound C2 formed one hydrogen bond with Ala128 amino acid and one pi–pi T-shaped bond with Tyr67 amino acid in the A chain of the targeted protein with a binding energy of −5.42 Kcal/mol. Meanwhile, the C3 compound was docked to the same protein, forming two hydrogen bonds with Arg346 and Gln302 residues and two pi–pi T-shaped bonds with Arg303 and Phe348 amino acid residues, with binding energy of −4.96 Kcal/mol.
Lastly, the second antidiabetic protein of human lysosomal acid α-glucosidase, encoded as 5NN5.pdb, was reacted with carvacrol (C2) and thymol (C3) with binding energies of −5.29 Kcal/mol and −5.72 Kcal/mol, respectively. One hydrogen bond and one pi–pi T-shaped bond were detected for carvacrol towards Leu868 and His717 amino acid residues, respectively. Three hydrogen bonds were created between thymol and Glu866, Ser864, and Arg594 amino acid residues of the targeted protein in the A chain, as shown in Figure 5.
Natural product-based treatments often have a favorable safety profile compared to synthetic drugs. EOs from various plants have shown potential in modulating glucose metabolism and improving insulin sensitivity, which are key factors in diabetes management [54]. These oils offer a natural approach to regulate blood glucose levels due to the metabolites present in them [55]. By exploring the antidiabetic properties of metabolites in the EOs, we can identify key residues that bind compounds in EOs and exhibit antiglycemic effects. This can pave the way for the development of therapies against diabetes mellitus. Since the antioxidant potential of O. compactum has also been demonstrated, this study also provides mechanistic information on the potential of O. compactum to manage oxidative-stress-allied diabetic issues. Natural products and, hence, EOs are generally well-tolerated and have fewer adverse effects, which is particularly beneficial for long-term use in chronic conditions like diabetes. They also offer the advantage of being easily accessible, cost-effective, and readily available in many regions, making them suitable for widespread use. Therefore, understanding the antidiabetic properties and binding mechanisms of O. compactum oil can pave the way for further exploration, potential optimization, and translation of its therapeutic benefits into clinical practice, offering new possibilities for managing and treating diabetes.

3. Materials and Methods

3.1. Chemicals

Anhydrous sodium sulfate (Na2SO4), α-amylase, α-glucosidase, acarbose, and dinitrosalicylic acid (DNS) were purchased from Sigma-Aldrich, Saint-Louis, American. All other used chemicals were of analytical grade.

3.2. Plant Material and EO Extraction

The aerial parts of Origanum compactum Benth. were collected from its natural environment in the province of Thar Es-Souk, north Morocco (34°39′03″ N, 4°16′40″ W). The botanical authenticity was confirmed by botanists from the Scientific Institute, University Mohamed V and a voucher number was provided (RAB 11421). The plant was dried at room temperature and the then extraction of oil was started. An amount of 100 g of dried aerial parts was distillated by hydro-distillation for 180 min using a Clevenger-type device. The obtained oil was recovered and dehydrated by anhydrous sodium sulfate, filtered, and then maintained at 4 °C, pending future assays.

3.3. GC-MS Analysis

The volatile content of O. compactum oil was characterized using chromatography (Trace GC-Ultra(Santa Clara, CA, USA) coupled with mass spectrometry (Quadrapole, Polaris Q (Santa Clara, CA, USA) (GC-MS) as described by Al-Mijalli [50,56,57]. The system is well-appointed with a non-polar HP-5MS capillary column (30 m, 0.32 mm × 0.25 µm). The temperature of the injector and detector was fixed at 280 and 300 °C, respectively. The column temperature was set at 50 °C for 5min and then at 180 °C for 4 °C/min. Helium (He) served as carrier gas (1.2 mL/min). A sample volume of 0.9 µL was injected manually. The chemical characterization of O. compactum oil constituents was undertaken via the comparison of its retention index (RI) (detected using a homologous series of C8–C24 alkanes) and its mass spectra (MS) fragmentation patterns to those described in the literature catalogues [58,59]. Furthermore, each component was measured based on internal normalization of the total area of peaks observed in each chromatogram. Then, component MS was completed as illustrated in chemical libraries (NIST LIBRARY Version 2.0, 1 July 2002) through computer matching.

3.4. In Vitro Antidiabetic Assay

The antidiabetic potential of O. compactum EO was assessed through antidiabetic assays, i.e., through inhibition of the enzymatic activity of α-amylase and α-glucosidase. This is a target-based standard method of determining antidiabetic potential of plant oil. The control drug acarbose (IUPAC name: O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl] amino]-α-D-glucopyranosyl-(1→4)-O-α-D-glucopyranosyl-(1→4)-D-glucopyranose) was purchased from Sigma-Aldrich. The procedure for antidiabetic assays is described below:

3.4.1. α-Amylase Inhibition Assay

The α-amylase activity was determined by modifying a previously described method [50]. First, 200 μL of EOs was mixed with 200 µL of substrate starch solution (1%) at 37 °C for 20 min. Then, 200 μL of α-amylase solution and 200 µL of 0.02 M phosphate buffer (pH = 6.9) were added. The mixture was incubated for 10 min at 37 °C. Then, 500 µL of dinitrosalicylic acid solution (DNS) was added to the mixture and boiled in a water bath at 100 ◦C for 8 min. Then, the solution was cooled by adding 2000 µL of distilled water. Absorbance of the solution was read at 540 nm. The α-amylase inhibitory activity was expressed as IC50 value (µg/mL).

3.4.2. α-Glucosidase Inhibition Assay

The α-glucosidase inhibitory activity was determined according to a previously described method [60], with slight modifications. EO (150 μL) was incubated with 100 µL of the enzymatic solution (α-glucosidase, 0.1 U/mL) for 10 min at 37 °C with an additional 200 μL of 1 mM pNPG (substrate) solution dissolved in 0.1 M sodium phosphate buffer and the mixture was incubated for 30 min at 37 °C. The reaction was terminated with the addition of 0.1 M of Na2CO3 (1 mL). The absorbance was measured at 405 nm. The α-glucosidase inhibitory activity was expressed as IC50 value (mg/mL).

3.5. ADMET Prediction

The effectiveness of a medication can be compromised by its restricted absorption, distribution, metabolism, elimination, and toxicity features, collectively referred to as its ADMET properties [61]. Additionally, the principal obstacle faced in drug development during clinical studies is the drug’s pharmacokinetic features, which can lead to significant expenses [62]. As a result, computational methods were utilized to evaluate the ADME characteristics of O. compactum essential oil to forecast its suitability as a potential candidate for drug development. The physicochemical properties of the studied molecules were initially predicted and Lipinski’s rule of five parameters [60] also validated. Subsequently, we examined the pharmacokinetic properties of absorption, distribution, metabolism, excretion, and toxicity (three toxicological features were chosen, AMES toxicity, hepatotoxicity, and skin sensitization of each chemical compound), using SwissADME [62] and pkCSM [63] online servers. Afterwards, we utilized a predictive model for the BOILED-Egg plot, which relied on calculating lipophilicity through the logarithm of the partition coefficient between n-octanol and water (Log P O/W), as well as assessing polarity using the topological polar surface area (TPSA) of small molecules. This approach was employed to identify highly probable central nervous system (CNS) agents capable of crossing the blood–brain barrier (BBB). Furthermore, we evaluated the oral bioavailability of the analyzed molecules. This was depicted as radar plots, comprising six physicochemical properties crucial for optimal oral bioavailability, i.e., lipophilicity (LIPO), polarity (POLAR), size (SIZE), solubility (INSOLU), saturation (INSATU), and flexibility (FLEX).

3.6. Molecular Docking Study

The molecular docking technique was applied to the candidate molecules of the O. compactum EO and the targeted human proteins in order to study the type of intermolecular interactions and their binding energies. Initially, the 3D crystal structures of three proteins, namely NADPH oxidase, human salivary amylase, and human lysosomal acid α-glucosidase, identified by the PDB IDs 2CDU, 1SMD, and 5NN5, were sourced from the Protein Data Bank (PDB). Specifically, the NADPH oxidase structure was selected for the investigation of antioxidant properties of major O. compactum compounds. These protein structures had been determined using X-ray diffraction techniques, resulting in resolutions of 1.80 Å, 1.60 Å, and 2.00 Å, respectively. The proteins of interest were initially processed using AutoDock 4.2 software [64]. This involved the removal of all co-crystallized ligands bound to the respective proteins, the addition of Gasteiger charges, and the elimination of any solvent water molecules. Subsequently, these prepared proteins were subjected to docking with the primary compounds from O. compactum EO that met Lipinski’s five rules. The docking procedure employed a grid box centered on the target protein, with dimensions set at a maximum of 126 units in each of the three dimensions and a spacing of 0.375 Å. Finally, the strongest ligand–protein complexes’ two- and three-dimensional interactions were visualized using Discovery Studio 2021 software [65].

3.7. Strengths and Weaknesses of Methodology

This study on the translational potential of O. compactum EO for diabetes mellitus treatment provided a coherent justification for further in vivo studies on the modulation of the activities of α-glucosidase and α-amylase by the oregano oil constituents. However, it would be beneficial to test the in vitro antidiabetic activities of single compounds of this oil to clearly elucidate their antidiabetic efficacy.
The original algorithm used in the present study that required various software techniques to predict the physio-chemical, toxicological, and biological properties highlighted the inner mechanisms involved in the induction of these characteristics and may represent a useful evaluation tool to be tested in in vivo evaluations of other natural products with biological activity. However, further in silico investigations targeting all compactum EO components are strongly required to fill knowledge gaps in the antidiabetic potential of this oil.

4. Conclusions

Research on EOs derived from plants and their metabolites has major implications in the field of therapeutic research. These EOs have been implicated to affect glucose metabolism, improve insulin sensitivity, and offer various therapeutic effects. This underscores their importance for further exploration. Our objective was to delve into the potential antidiabetic properties of O. compactum EO and understand the binding mechanism of its key metabolites, carvacrol and thymol, with human enzymes such as NADPH oxidase, α-glucosidase, and salivary amylase. The EO showed promising results due to its positive impact on glucose metabolism, insulin sensitivity, and related parameters and could serve as an effective antidiabetic agent. ADMET and binding residue information was also derived for the metabolites through computational assays. Binding site residues were identified through molecular docking. Such findings open avenues for future research to investigate this oil and its major bioactive compounds for their potential antidiabetic properties. Our findings can contribute to the development of natural-product-based interventions that are safe, effective, and targeted specifically towards key biological pathways involved in diabetes. We also propose similar studies on other unexplored EOs of plants used for antidiabetic treatment in traditional medicine. However, further in vivo investigations are strongly required to confirm the results of in vitro antidiabetic effect of O. compactum EO.

Author Contributions

Conceptualization, N.E.H. and H.N.M.; data curation, A.E. and M.J.; formal analysis, A.A.-F., H.N.M., H.A., N.E.H., H.O. and M.E.f.; funding acquisition; A.A., H.A. and E.E.M.; investigation A.A., A.Q., A.E. and A.A.-F.; methodology, H.N.M., N.E.H. and A.E.; resources, A.A.-F., H.N.M., A.Q. and H.A.; software, O.A.A., H.A., S.M.A. and M.J.; supervision, H.N.M. and N.E.H.; validation A.A.-F., H.A., H.N.M. and A.E.; visualization, A.A.-F., S.M.A., O.A.A. and E.E.M.; writ-ing—original draft, N.E.H., H.A., M.E.f. and S.M.A.; writing—review and editing A.A.-F., O.A.A., H.N.M. and N.E.H. All authors have read and agreed to the published version of the manuscript.

Funding

The authors extend their appreciation to the Deanship for Research & Innovation, Ministry of Edu-cation in Saudi Arabia for funding this research work through the project number: IFP22UQU4310026DSR074.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Catalysts 13 01429 g001
Figure 1. The BOILED-Egg model of four chemical compounds.
Figure 1. The BOILED-Egg model of four chemical compounds.
Catalysts 13 01429 g001
Catalysts 13 01429 g002
Figure 2. The bioavailability radars of the studied molecules, taking into account six physicochemical properties ideal for oral bioavailability, namely lipophilicity (LIPO), polarity (POLAR), size (SIZE), solubility (INSOLU), saturation (INSATU), and flexibility (FLEX).
Figure 2. The bioavailability radars of the studied molecules, taking into account six physicochemical properties ideal for oral bioavailability, namely lipophilicity (LIPO), polarity (POLAR), size (SIZE), solubility (INSOLU), saturation (INSATU), and flexibility (FLEX).
Catalysts 13 01429 g002
Catalysts 13 01429 g003
Figure 3. The 2D and 3D visualizations of intermolecular interactions established between NADPH oxidase protein (2CDU.pdb) towards carvacrol (C2) and thymol (C3) compounds, with binding energies of −6.26 Kcal/mol and −5.83 Kcal/mol, respectively.
Figure 3. The 2D and 3D visualizations of intermolecular interactions established between NADPH oxidase protein (2CDU.pdb) towards carvacrol (C2) and thymol (C3) compounds, with binding energies of −6.26 Kcal/mol and −5.83 Kcal/mol, respectively.
Catalysts 13 01429 g003
Catalysts 13 01429 g004aCatalysts 13 01429 g004b
Figure 4. The 2D and 3D visualizations of intermolecular interactions established between human salivary amylase protein (1SMD.pdb) towards carvacrol (C2) and thymol (C3) compounds, with binding energies of −5.42 Kcal/mol and −4.96 Kcal/mol, respectively.
Figure 4. The 2D and 3D visualizations of intermolecular interactions established between human salivary amylase protein (1SMD.pdb) towards carvacrol (C2) and thymol (C3) compounds, with binding energies of −5.42 Kcal/mol and −4.96 Kcal/mol, respectively.
Catalysts 13 01429 g004aCatalysts 13 01429 g004b
Catalysts 13 01429 g005aCatalysts 13 01429 g005b
Figure 5. The 2D and 3D visualizations of intermolecular interactions established between human lysosomal acid α-glucosidase protein (5NN5.pdb) towards carvacrol (C2) and thymol (C3) compounds, with binding energies of −5.29 Kcal/mol and −5.72 Kcal/mol, respectively.
Figure 5. The 2D and 3D visualizations of intermolecular interactions established between human lysosomal acid α-glucosidase protein (5NN5.pdb) towards carvacrol (C2) and thymol (C3) compounds, with binding energies of −5.29 Kcal/mol and −5.72 Kcal/mol, respectively.
Catalysts 13 01429 g005aCatalysts 13 01429 g005b
Table 1. Chemical composition of O. compactum EO.
Table 1. Chemical composition of O. compactum EO.
No aCompounds bKI cMolecular Formula% Relative Peak Area
1α-Thujene923C10H160.41
2α-Pinene979C10H160.17
3p-Cymene1026C10H167.12
4α-Phellandrene1035C10H160.54
5Linalool1098C10H18O2.64
6α-Terpineol1185C10H18O0.28
7Thymol1290C10H14O54.6
8Carvacrol1298C10H14O23.18
9β-Caryophyllene1494C15H243.37
10Caryophyllene oxide1573C15H24O5.34
Total identified % 97.65
Monoterpene hydrocarbons 8.24
Oxygenated monoterpenes 80.7
Sesquiterpene hydrocarbons 3.37
Oxygenated sesquiterpenes 5.34
a In order of elution on HP-5Ms. b Compounds identified according to KI and MS. c Retention index established from alkane series on HP-5 MS capillary column (C8–C24).
Table 2. Antidiabetic activity of O. compactum EOs against the enzymes α-amylase and α-glucosidase.
Table 2. Antidiabetic activity of O. compactum EOs against the enzymes α-amylase and α-glucosidase.
SamplesIC50 (µg/mL)
α-Amylaseα-Glucosidase
O. compactum EO150.11 ± 0.12119.84 ± 0.22
Acarbose (control)98.24 ± 0.030.02
Table 3. The prediction of physicochemical properties of four compounds, based on Lipinski rules.
Table 3. The prediction of physicochemical properties of four compounds, based on Lipinski rules.
Compound NumbersPhysico-Chemical PropertiesLipinski Rules
Molecular Weight (g/mol)Molar Refractive IndexRotatable BondsLog P (Octanol/Water)H-BAH-BDCategorical (Yes/No)
Rule≤50040 ≤ MR ≤ 130<10<5≤10<5Yes/No
C1150.2248.0112.2411Yes
C2220.3568.2703.1510Yes
C3134.2245.9912.5100Yes
C4150.2248.0112.3211Yes
Table 4. The prediction of ADMET in silico pharmacokinetic properties of four compounds.
Table 4. The prediction of ADMET in silico pharmacokinetic properties of four compounds.
Hepatotoxicity AbsorptionDistributionMetabolismExcretionToxicity
Intestinal Absorption BBB
Permeability		CNS PermeabilitySubstrateInhibitorTotal ClearanceAMES
Toxicity 		HepatotoxicitySkin Sensitization
Cytochromes
2D63A41A22C192C92D63A4
Numeric (% Absorbed)Numeric (Log BB)Numeric (Log PS)Categorical (Yes/No)Numeric (Log mL/min/kg)Categorical (Yes/No)
C193.7120.381−1.438NoNoNoNoNoNoNo0.243NoNoYes
C296.0660.654−2.525NoNoYesYesYesNoNo0.905NoNoYes
C395.520.541−1.348NoNoYesNoNoNoNo0.239NoNoYes
C493.240.366−1.349NoNo YesNoNoNoNo0.259NoNoYes
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MDPI and ACS Style

Assaggaf, H.; El Hachlafi, N.; El fadili, M.; Elbouzidi, A.; Ouassou, H.; Jeddi, M.; Alnasser, S.M.; Qasem, A.; Attar, A.; AL-Farga, A.; et al. GC/MS Profiling, In Vitro Antidiabetic Efficacy of Origanum compactum Benth. Essential Oil and In Silico Molecular Docking of Its Major Bioactive Compounds. Catalysts 2023, 13, 1429. https://doi.org/10.3390/catal13111429

AMA Style

Assaggaf H, El Hachlafi N, El fadili M, Elbouzidi A, Ouassou H, Jeddi M, Alnasser SM, Qasem A, Attar A, AL-Farga A, et al. GC/MS Profiling, In Vitro Antidiabetic Efficacy of Origanum compactum Benth. Essential Oil and In Silico Molecular Docking of Its Major Bioactive Compounds. Catalysts. 2023; 13(11):1429. https://doi.org/10.3390/catal13111429

Chicago/Turabian Style

Assaggaf, Hamza, Naoufal El Hachlafi, Mohamed El fadili, Amine Elbouzidi, Hayat Ouassou, Mohamed Jeddi, Sulaiman Mohammed Alnasser, Ahmed Qasem, Ammar Attar, Ammar AL-Farga, and et al. 2023. "GC/MS Profiling, In Vitro Antidiabetic Efficacy of Origanum compactum Benth. Essential Oil and In Silico Molecular Docking of Its Major Bioactive Compounds" Catalysts 13, no. 11: 1429. https://doi.org/10.3390/catal13111429

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