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Article

In Vitro and In Silico Evaluations of Boswellia carterii Resin Dermocosmetic Activities

by
Sohaib Hourfane
1,
Hicham Mechqoq
1,
Fatima Errajouani
2,
João Miguel Rocha
3,4,* and
Noureddine El Aouad
1,*
1
Research Team on Natural Products Chemistry and Smart Technology (NPC-ST), Polydisciplinary Faculty of Larache, Abdelmalek Essaadi University, Tetouan 93000, Morocco
2
Service de la pharmacie centrale, Centre Hospitalier Universitaire Mohamed VI, Tanger 90000, Morocco
3
Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal
4
Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal
*
Authors to whom correspondence should be addressed.
Cosmetics 2022, 9(6), 131; https://doi.org/10.3390/cosmetics9060131
Submission received: 16 October 2022 / Revised: 28 October 2022 / Accepted: 18 November 2022 / Published: 2 December 2022
Browse Figures
Versions Notes

Abstract

:
Boswellia carterii is a plant species belonging to the Burseraceae family. It grows up in trees or shrubs, and it is known for producing an aromatic resin commonly named frankincense or olibanum. This resin has been used in traditional medicine to treat various conditions such as inflammations, gastrointestinal disorders and traumatic injuries. Virtual screening and molecular docking are two in silico approaches used to predict potential interactions between ligands and the active site of a protein. These approaches are mainly used in natural product chemistry and pharmacology as a screening tool to select plant extracts or fractions for in vitro testing, as well as for the prediction of mechanisms of action. The aim of this research is the in silico and in vitro evaluations of the potential collagenase and elastase inhibitory activities of Boswellia carterii resin organic extracts (viz., methanol, n-hexane and ethyl acetate). The obtained results revealed that methanol and n-hexane exhibited the best collagenase inhibitory activity with values superior to 85%, whereas the methanol and ethyl acetate showed the highest elastase inhibition activity with inhibition values ranging between 40 and 60%. The molecular docking prediction confirmed the experimental results; moreover, the visualization of the ligand–protein interactions showed that the main compounds of the organic extracts may have mechanisms of action similar to the positive controls. Those findings are very promising and open new perspectives for the exploitation of Boswellia carterii resin as active agents for the development of anti-aging cosmeceuticals.

1. Introduction

Plants have always been considered a rich resource of natural compounds [1]. Those natural products often present many advantages such as low toxicity, bioavailability and structural diversity [2]. For the last 50 years, those natural substances have been exploited for the development of pharmaceutical and cosmetical products [3,4,5]. Nowadays, many research groups investigate plant-based secondary metabolites for the research of new drug candidates, or active agents for the development of cosmetic products for skin care [6].
The resinous metabolites commonly known as frankincense or olibanum are produced by trees of the genus Boswellia (Figure 1). Such metabolites have attracted increasing popularity over the last decade due to their various pharmacological activities [7,8,9].
The genus Boswellia belongs to the Burseraceae family and is represented by ca. 25 species [10]. This plant family is distributed from tropical Africa to Asia and is characterized by the presence of resin ducts in the barks, which produce pleasant-smelling oleo-gum resins known as frankincense or olibanum, in Arabic, and luban, in Jibali and Dhofari Arabic [11]. Boswellia carterii, a plant species belonging to the family Burseraceae, is well known for its ability to secrete a gum resin from the bark, which was known as olibanum [12]. The gum resin of Boswellia carterii has been used in traditional medicine. Indeed, traditional practices have referred to the use of Boswellia carterii to treat various diseases, such as inflammatory, gastrointestinal disorders, and traumatic injuries [9].
Boswellia carterii is a deciduous tree, 2 to 8 m high, with one or more trunks extending from the base, and its bark is thick, grey, and parchment like. It has compound leaves and an odd number of leaflets (9 to 15), which grow opposite along its branches. The small, yellowish-white flowers appear in the leaf axils. The flowers are composed of five petals, ten stamens, and a five-toothed calyx. The fruit is a capsule measuring approximately 1 cm in length [13].
Over the past two decades, scientific research provided increasing evidences of the therapeutic potential of Boswellia carterii. The available literature mentions the presence of terpenoids as main compounds, which proved to have strong anti-inflammatory [14], cytotoxic [8], hepatoprotective [8], antibacterial [15] and antifungal [7] activities.
The present research aims at extracting and evaluating the dermocosmetic potential of Boswellia carterii gum-resin organic extracts. The dermocosmetic activities were evaluated through monitoring the in vitro inhibition of collagenase and elastase. The main compounds of the Boswellia carterii resin extracts were selected from the literature and subjected to in silico study by molecular docking to identify their mechanisms of action.

2. Material and Methods

2.1. Chemicals and Reagents

Ethyl acetate (EtOAc), n-hexane (n-hex), methanol (MeOH), sodium carbonate (Na2CO3), Folin–Ciocalteau reagent and gallic acid were obtained from Alfa Aesar GmbH & Co. (Karlsruhe, Germany). For collagenase inhibition assay, collagenase from Clostridium histolyticum (≥1 FALGPA units/mg; EC number: 232-582-9), fluorogenic substrate peptide MMP-2, and chlorhexidine were acquired from Sigma-Aldrich, (Paris, France). Finally, porcine pancreatic elastase type IV (≥ 4 units/mg protein; EC Number 254-453-6), fluorogenic substrate (EC Number 257-823-5), tris(hydroxymethyl)aminomethane hydrochloride (Trizma-HCl), and elastatinal were purchased from Sigma-Aldrich.

2.2. Plant Material and Extract Preparation

The resin of Boswellia carteri (31.5 g) was pulverized and extracted three times with Soxhlet (5 h). The methanolic extract was dried giving a solid (20.32 g). Furthermore, 1.43 g of the methanolic extract were stored. Then, the dry extract was submitted to a liquid/liquid partition in n-hexane–MeOH (50:50, v/v), giving the n-hexane (11.06 g) and MeOH (7.86 g) fractions. The latter was re-partitioned in EtOAc–H2O (50:50, v/v), yielding to EtOAc (6.95 g) and aqueous extract. The extracts were dried with a rotavapor (BUCHI R-100, Flawil, Switzerland) and stored at 0 °C.

2.3. Enzymes Inhibition Activities

2.3.1. Collagenase Inhibition Assay

The collagenase inhibitory potential was determined using the spectrometric method previously described by Mechqoq et al. [16]. Briefly, collagenase enzyme from Clostridium histolyticum was prepared in Trizma-base buffer (15 mM, pH = 7.3). In a 96-well microplate, 120 μL of buffer, 40 μL of sample and 40 μL of collagenase enzyme solution (60 μg/mL) were mixed and incubated at 37 °C for 10 min. The fluorogenic substrate (40 µL) was added, and then incubated at 37 °C for 30 min. The fluorescent intensity was measured at excitation and emission wavelength of 320 and 405 nm, respectively, using an Infinite 200 PRO series (Tecan) plate reader. Experiments were performed in triplicate. The samples were evaluated at 200 μg/mL. Chlorhexidine was used as a positive control of the assay (IC50 = 50 μM) [17]. The inhibition percentage of collagenase was calculated by the Formula (1):
Collagenase   inhibition   ( % ) = ( F c   -   F c   b l a n k )   -   ( F s   -   F s   b l a n k ) ( F c   -   F c   b l a n k )   × 100
where Fc is the fluorescence of buffer, collagenase, sample solvent and substrate, and Fs is the absorbance of buffer, collagenase, sample or chlorhexidin, and substrate. The blanks contained all the components except the enzyme.

2.3.2. Elastase Inhibition Activity

Elastase inhibition activity was evaluated according to a method previously described by Angelis et al. [18]. Prior to the experiments, porcine pancreatic elastase type IV and N-succinyl-Ala-Ala-Ala-p-nitroanilide were dissolved in Trizma-base buffer (50 mM, pH = 7.5). Then, 70 μL of Trizma-base buffer, 10 μL of the samples and 5 μL of elastase (0.45 U/mL) were mixed and incubated in a 96-well microplate for 10 min in the dark. Then, 20 μL of substrate (2 mM) were added in each well and the microplate was incubated for 30 min. The absorbance was measured at 405 nm with an Infinite 200 PRO (Tecan) plate reader. The samples were evaluated at 200 µg/mL. Then, the most promising ones were evaluated at lower concentrations to determine the IC50 values [17]. Elastatinal was used as a positive control, being a strong competitive inhibitor of elastase (IC50 = 0.5 μg/mL). Experiments were performed in triplicate. The inhibition percentage of elastase was calculated according to the Formula (2):
Elastase   inhibition   ( % ) = ( F c   -   F c   b l a n k )   -   ( F s   -   F s   b l a n k ) ( F c   -   F c   b l a n k )   × 100
where Fc is the absorbance of the elastase in the buffer, sample solvent and substrate, and Fs is the absorbance of the elastase in the buffer, samples or elastatinal and substrate. The blanks contained all the components except the enzyme.

2.4. Statistical Analysis

All experimental data were expressed as the mean ± standard deviation by measuring three independent replicates. Means were compared statistically using the STATICA program v6.1, (Statsoft, Inc., Palo Alto, CA, USA) with Student’s t-test (significance level p < 0.05).

2.5. In Silico Studies

2.5.1. Virtual Screening

Virtual screening is a well-known computational approach used to select promising compounds for drug discovery. It consists of medium-precision dockings of a compound library against a protein, in order to identify ligands with high affinity. In this study, the virtual screening was carried out using PyRx v0.8 (The scripps Research Institute, La Jolla, San Diego, CA, USA) [19]. It selected 17 of the most abundant compounds of Boswellia carterii resin and screened them against collagenase and elastase.
The tridimensional structures of the selected ligands were downloaded from PubChem (http://pubchem.ncbi.nlm.nih.gov, accessed 6 October, 2022), namely 11-keto-beta-boswellic acid (1) (PubChem CID: 6918114), acetyl-11-keto-beta-boswellic acid (2) (PubChem CID: 71463896), beta-boswellic acid (3) (PubChem CID: 168928), alpha-boswellic acid (4) (PubChem CID: 637234), alpha-acetyl boswellic acid (5) (PubChem CID: 117072585), beta-acetyl boswellic acid (6) (PubChem CID: 11386458), 3-oxotirucallic acid (7) (PubChem CID: 134693088), elemonic acid (8) (PubChem CID: 15559100), 3-beta-hydroxytirucallic acid (9) (PubChem CID: 441677), palmitic acid (10) (PubChem CID: 985), lupeol (11) (PubChem CID: 259846), incensole (12) (PubChem CID: 44583885), incensole acetate (13) (PubChem CID: 73755086), 3alpha-hydroxytirucalla-7,24-dien-21-oic acid (14) (PubChem CID: 158143), lupeolic acid (15) (PubChem CID: 12111950), acetyl-9,11-dehydro-beta-boswellic acid (16) (PubChem CID: 44558899) and 9,11-dehydro-beta-boswellic acid (17) (PubChem CID: 102509765) (Figure 2). Regarding the structures of the collagenase (PDB CID: 1CGL) and elastase (PDB CID: 1BRU), they were downloaded from the RCSB Protein Data Bank (http://www.rcsb.org/, accessed 6 October, 2022).
The proteins were downloaded in PDB format and the ligands in SDF format, the structures were prepared and processed on PyRx using the software internal openbabel and Autodock extension. The ligands that showed the best results were submitted to a molecular docking study.

2.5.2. Molecular Docking

The molecular docking study was performed to investigate the binding mode between eight most common molecules (ligands) in resin extract of Boswellia carterii [20,21,22] (namely, 11-Keto-beta-boswellic acid, Acetyl-11-keto-beta-boswellic acid, beta-Boswellic acid, alpha-Boswellic acid, alpha-acetyl boswellic acid, and beta-acetyl boswellic acid) and two enzymes (collagenase and elastase) using Autodock Vina v1.1.2 (The scripps Research Institute, La Jolla, San Diego, CA, USA) [23].
The docking input files of both proteins and ligands were generated using AutoDockTools v1.5.6 package (The scripps Research Institute, La Jolla, San Diego, CA, USA) [24,25]. The proteins were prepared by removing water molecules and merging non-polar hydrogen atoms, when the ligands had their rotatable bonds defined. The search grid of the key site of collagenase search grid has been set as center x: 30.681, center y: 46.555, and center z: −0.0090, with dimension size x,y,z: 60. The elastase search grid parameters corresponds to center x: 23.204, center y: 47.660, and center z: 17.090 with dimensions size x,y,z: 25. Docking accuracy has been increased by adjusting the energy range to 10 and the exhaustiveness value to 300.
After docking simulations, the best scoring pose was chosen using PyMoL 1.7.6 software (http://www.pymol.org/, accessed 8 October, 2022). Then, the ligand–protein interactions were analyzed and visualized using the BIOVIA Discovery Studio Visualizer 21.1.0.0 software (https://discover.3ds.com/discovery-studio-visualizer-download, accessed 8 October, 2022).

2.5.3. Molecular Proprieties Prediction

The evaluation of compound’s safety and pharmacological proprieties has become an important issue. These parameters are determined during the preclinical testing and are considered the most critical stages in drug discovery. As a matter of fact, these tests aim at selecting active compounds with low toxicity and better absorbance and bioavailability.
Nowadays, many prediction tools are widely used in natural products chemistry. These tools involve algorithms based on chemical studies and aims to give a base to set up laboratory experiments. OSIRIS Property Explorer (free online program) is one of these tools. It is a java-based application developed and operated by the pharmaceutical firm “Actelion”, that can calculate the molecular properties of a molecule (Toxicity, clogP, MW, drug-likeness) [26]:
  • Toxicity risk: This parameter indicates if a compound may be harmful. Additionally, it provides the risk category. The prediction of toxicity risk is by no means intended to be entirely reliable. However, the reliability of this tool has previously been assessed by Osman et al. [27], where a set of toxic compounds were evaluated for their potential mutagenic effect. This study showed that 86% of these structures had a high or medium risk of being mutagenic.
  • Partition coefficient (cLogP): The partition coefficient is the ratio of the equilibrium concentrations of a solute between the apolar organic and aqueous phases. This coefficient is defined as the logarithm of the octanol/water partition coefficient (Coctanol/Cwater), and gives an idea of the relative range between the water solubility of a substrate and its absorption by the human body in the intestines [28]. Molecules with clogP values above zero are likely to be lipophilic, while those with the clogP values below zero may be hydrophilic.
  • Molecular weight (MW): This is the sum of the atomic weights of the atoms making up the molecule. This parameter is very useful for studying the diffusion and action mode of a compound. Molecules with high MW values may not be well absorbed and fail to reach their action site. Thus, it is very important to have low molecular weight values. For orally administered drugs, the molecular weight of the active ingredient should be less than or equal to 500 Daltons, with the optimal value around 300 Daltons [29].
  • Drug-likeness: The similarity of a molecule to a drug (or drug likeliness) can be defined as a complex balance of several molecular properties and structural features that can establish whether a molecule is similar to a known drug. These properties are mainly hydrophobicity, size and flexibility of the molecule, as well as the presence of pharmacophore characteristics influencing the behavior of the molecule in a living organism, including bioavailability, transport, protein affinity, reactivity, and toxicity. This parameter can be very handy when it comes to predicting permeability through gastrointestinal epithelial cells and the blood–brain barrier. Moreover, it can help to interpret pharmacokinetic results and understand the behavior of a molecule in the body [30].
  • Drug score: This score combines all the above parameters into a value used to assess the overall potential of a compound [31]. Indeed, a molecule with a global score equal to or higher than 0.5 is potentially promising for the development of a future drug or for its use as an ingredient.

3. Results and Discussion

3.1. Enzyme Inhibition Assays

The methanol extract obtained from Boswellia carterii resin as well as its fractions (ethyl acetate, n-hexane and aqueous) recovered after solvent partition were evaluated for their collagenase and elastase inhibition activities. These evaluations were performed for both enzymes, with a concentration of extracts of 200 μg/mL. Figure 3 and Figure 4 reveal the inhibition percentages of the evaluated extracts against collagenase and elastase.
The highest collagenase inhibitory activities were observed with the Boswellia carterii resin methanol extract and the n-hexane fraction, with values ranging between 87 and 95%, followed by ethyl acetate and aqueous fractions with 65.01 ± 2.98% and 13.49 ± 3.93%, respectively (Figure 3). The n-hexane, ethyl acetate and aqueous fractions were all obtained from the methanolic extract of the resin. The analysis of these results shows that, the methanolic extract active compounds have been retrieved on the n-hexanic and ethyl acetate fractions.
For the elastase inhibition assay, all the tested extracts showed inhibition values lower than 60% (Figure 4). Moreover, the methanolic crude extract and ethyl acetate fraction exhibited the highest inhibition values with 56.42 ± 3.74% and 42.98 ± 3.18%, respectively. followed by the n-hexane and aqueous fractions, with values ranging between 5 and 25%. In a study conducted by Badria et al. [20], the methanolic extract of Boswellia carterii has been fractionated using the same approach adopted in this study. According to these authors, the ethyl acetate fraction is characterized by the presence of 11-keto-beta-boswellic acid, which is probably responsible of the elastase inhibition activity.
Collagen and elastin are the main fibers that form the extracellular matrix of the skin, the former being responsible for tensile strength, whereas the other provides elasticity. The aging process is accompanied by the decrease in production and strength of collagen and elastin, causing the appearance of wrinkles [32]. Further, the production of collagenase and elastase (two enzymes responsible of collagen and elastin degradation) is also responsible of the skin intrinsic aging [33].
The resin of Boswellia carterii is a frequent component in the traditional Chinese herbal medicine [34]. Several studies conducted on this plant material reported the presence of many compounds such as polyphenols and terpenoids [20,21,35,36]. Such terpenoids are mainly represented by boswellic acids, and are considered as the most active constituents of Boswellia resin [37].
In a paper published by Garg [38], the authors described the antioxidant activity of polyphenols. The same paper featured the investigation of antioxidant potential of terpenoids and proved that these compounds are highly active and can contribute to the delay of skin aging. Additionally, a molecular docking investigation conducted by Yasmeen and Gupta [39] reported the anti-collagenase activity of some terpenoids (lupeol, lupeol acetate, betulin and phytol). According to this study, the lupeol exhibited the highest binding affinity with a score of −8.24 kcal/mol, and this value was higher than the reference drug (doxycycline = −8.05 kcal/mol). However, lupeol acetate and phytol displayed values near to −7.00 kcal/mol, whereas betulin showed the lowest value with −4.66 kcal/mol. This study concluded that the hydroxyl groups present in the ligands play a substantial role in establishing the protein/ligand interaction via hydrogen bonds.
Furthermore, the elastase inhibitory activity of triterpenoids and terpenoids had been reported as well. According to Mawarni et al. [40], the terpenoids contained in the petals and receptacle of rose flower (Rosa damascena) extracts showed moderate elastase inhibition potential with values above 70% for an extract concentration of 66.67 µg/mL.
Despite ethnobotanical studies report the dermocosmetic properties of Boswellia resin [41], the literature does not mention any investigation of potential collagenase and elastase inhibitory activities. This article is the first research study mentioning the presence of aging enzyme inhibitory activity.

3.2. In Silico Studies

3.2.1. Virtual Screening

Virtual screening combined to molecular docking analysis is an effective method to select potential drug candidates and predict their binding parameters. So far, this approach proved to be applicable on the field of drug discovery, and has been used successfully in many applications [16,42,43].
In this study, PyRx was used to screen 17 molecules (Figure 1) previously identified in Boswellia carterii resin against the collagenase and elastase. Results of the virtual screening are summarized in Table 1.
The collagenase and elastase virtual screening results (Table 1) show that the evaluated compounds have different score values. The lowest score value (in Kcal/mol) corresponds to the best chemical affinity with the enzyme. For the collagenase, the highest score value was observed with 9,11-dehydro-beta-boswellic acid (−11.0 Kcal/mol), followed by the acetyl-9,11-dehydro-beta-boswellic acid, alpha-boswellic acid and elemonic acid, with values ranging between 10.3 and 10.6 Kcal/mol. With regard to the elastase (Table 1), the highest affinity was recorded for acetyl-beta-boswellic acid (−6.6 kcal/mol), followed by 3-alpha-hydroxytirucalla-7,24-dien-21-oic acid (6.4 Kcal/mol), along with lupeolic acid and 3-beta-hydroxytirucallic acid (both with a score of −6.2 Kcal/mol).
The previous in vitro evaluation of the collagenase and elastase inhibitory activities showed that n-hexane and ethyl acetate extracts were the most biologically active. The extraction procedure adopted on this research effort was similar to the one described by Banno et al. [21]. According to these last authors, the n-hexane extract is rich in elemonic acid, acetyl-alpha-boswellic acid, acetyl-beta-boswellic acid, acetyl 11-keto-beta-boswellic acid, palmitic acid, as well as beta- and alpha-boswellic acids, whereas the ethyl acetate extract is mainly represented by the acetyl 11-keto-beta-boswellic acid, 11-keto-beta-boswellic acid and alpha-boswellic acid.
The presence of these compounds may explain the collagenase and elastase inhibitory activities. Subsequently, the eight lead compounds of Boswellia carterii n-hexane and ethyl acetate extracts were considered as promising candidates for further analysis.

3.2.2. Molecular Docking

Molecular docking is a computational modelling method that allows compounds to be screened in silico before testing experimentally. Currently, it is the best alternative to rapidly predict binding conformations of ligands that are energetically favorable to interact with a pharmacological receptor site. In this study, the molecular docking was applied to compare the binding energies and amino acids involved in the ligand–protein interaction. Table 2 summarizes the results of these simulations.
The results of the molecular docking simulations with collagenase (Table 2) showed that the ligands with the best scores are the elemonic and alpha-boswellic acids (−10.4 and 10.0 Kcal/mol, respectively). They were followed by beta-boswellic, acetyl-alpha-boswellic and 11-keto-beta-boswellic acids, with a score of −9.6 Kcal/mol.
The visualization of the amino acids involved in the ligand–protein interaction of collagenase shows that some amino acids are common to all compounds. For example, Pro238 binds to all compounds, the same for His228 but this time excluding the elemonic acid (Figure 5). Moreover, Asn180 is common to acetyl 11-keto-beta-boswellic acid, 11-keto-beta-boswellic acid and elemonic acid. Concerning acetyl-beta-boswellic acid and acetyl-alpha-boswellic acid, they have shared four amino acids, namely Leu181, His218, His222, His228 and Pro238 but also, they are different at the level of one amino acid, viz. His218 for acetyl-beta-boswellic acid and Val215 for acetyl-alpha-boswellic acid. Finally, acetyl 11-keto-beta-boswellic acid, 11-keto-beta-boswellic acid shared the same amino acids and the same also for alpha-boswellic acid and beta-boswellic acid. These results show that those compounds have similarities on their binding sites, which may suggest that they may have similar inhibition mechanisms of action.
The Boswellia carterii resin n-hexane fraction showed the highest in vitro inhibitory activity at concentration of 200 μg/mL, according to by Banno et al. [21]. This fraction is rich in acetyl 11-keto-beta-boswellic acid (23.23%), acetyl-beta-boswellic acid (15.7%) and elemonic acid (14.79%). The latter showed the highest affinity with collagenase. The inhibitory activity may be probably due to the presence of those compounds or to their synergetic action.
The ligands/elastase docking simulations (Table 2) show that the obtained score values were lower in comparison with the collagenase simulations. However, the highest affinity was recorded by acetyl 11-keto-beta-boswellic acid (with a score of −8.2 Kcal/mol) followed by acetyl-beta-boswellic acid (−7.9 Kcal/mol), whereas 11-keto-beta-boswellic and elemonic acids showed a score value of −7.4 Kcal/mol. These values were the lowest compared to the other ligands and suggest that these compounds may have a very strong affinity to the elastase.
For elastase, the amino acid Leu99 is binding with all compounds except alpha-boswellic acid and acetyl alpha-boswellic acid (Figure 6). On the other hand, His57 is common to alpha-boswellic acid, acetyl-alpha-boswellic acid, 11-keto-beta-boswellic and elemonic acid. Ser195 and Gly216 are both found in acetyl-beta-boswellic acid and acetyl-11-keto-beta-boswellic acid. However, these two amino acids are also found alone, Gly216 on acetyl-alpha-boswellic acid, and Ser195 in elemonic acid.
Boswellia carterii resin ethyl acetate fraction showed a good elastase in vitro inhibitory activity with a value up to 40% of inhibition, at a concentration of 200 µg/mL. The chemical composition of this fraction has been reported by Banno et al. 2006 [11]. This extract is rich in acetyl 11-keto-beta-boswellic acid (14.09%), alpha-boswellic acid (13.35%) and beta-boswellic acid (8.12%). The main compound of this fraction, i.e., acetyl 11-keto-beta-boswellic acid, showed the highest affinity to elastase. The elastase inhibitory activity is probably due to the presence of this molecule in the ethyl acetate fraction, or to other compounds under single or synergetic actions.
The analysis of literature shows the absence of data regarding molecular docking simulation of Boswellia carterii resin compounds against collagenase or elastase. However, some studies reported the potential inhibition activity of other terpenoid against collagenase and elastase [38,39,40]. Nevertheless, molecular docking studies have been performed on boswellic acids and their derivatives. These studies were focused on the anti-inflammatory [44], antidiabetic [45,46], anticancer [47], SARS-CoV-2 antiviral [48] activities. Our current study is the first reporting in vitro and in silico evaluations of the inhibition potential of Boswellia carterii resin against elastase and collagenase.

3.2.3. Molecular Proprieties Prediction

In order to check the safety of use of the studied compounds, they have been submitted to the prediction of molecular parameters. The OSIRIS program makes possible to predict the molecular characteristics of a molecule, which include toxicity risks, lipophilicity (clogP), solubility and molecular weight. The program also allows to estimate the degree of similarity of the molecule with different drugs already existing in the market (drug-likeness). Table 3 shows the prediction results of each ligand.
The chemical parameters generated by OSIRIS show that all tested molecules, except elemonic and palmitic acids, can be used without any risk of toxicity. The use of elemonic and palmitic acids in their pure state could be potentially dangerous. However, the presence of these compounds in a mixture in a plant extract considerably reduces their potential danger. Indeed, several studies have shown the toxicity of elemonic and palmitic acids based on their toxicity assessment [7,49,50].
All molecules showed relatively similar theoretical values of lipophilicity (ClogP) and solubility (S) (Table 3). These values suggest that these parameters will not have a significant effect on the docking of molecules with proteins during the docking step.
All the molecules have more or less similar molecular weights between 450 and 515 g/mol, with the exception of palmitic acid which has the lowest molecular weight of 256 g/mol. These molecules have relatively low molecular weights facilitating their absorption in the intestine. Conversely, molecules with very high molecular weights cannot be absorbed in the intestine [51].
The tested molecules showed a low drug-likeness score. The highest value was observed for acetyl 11-keto-beta-boswellic acid with −1.72. On the other hand the lowest value was observed for palmitic acid with −25.22. Such findings suggest the non-resemblance of these molecules with the existing drugs in the market.
The drug score is calculated from all these parameters, specifically the risks of toxicity and bioavailability. The molecule showing the most interesting drug score is 11-keto-beta-boswellic acid, with a value of 0.21. Nevertheless, the other molecules have similar values, between 0.14 and 0.18, except for elemonic and palmitic acids which have the lowest value of 0.09. This is mainly due to the presence of a double toxicity risk influencing considerably on the drug potential of these two molecules.

4. Conclusions

In conclusion, the methanol extract and the n-hexane fraction exhibited the best collagenase inhibitory activity with values higher than 85%, whereas the ethyl acetate fraction showed the highest elastase inhibition activity, with inhibition values ranging between 50 and 60%. The in silico study was carried out in order to ascertain the toxicity risks, the biodisponibility and the mechanism of action behind the inhibitory activity of the Boswellia carterii resin extracts. The resin main compounds were submitted to virtual screening with collagenase and elastase using PyRx. To that purpose, the eight most promising compounds underwent a thorough study to determine their mechanism of action, toxicity risk and bioavailability. The obtained results showed that elemonic acid has the highest affinity with collagenase, whereas acetyl 11-keto-beta-boswellic acid has the highest affinity with elastase. These results support the in vitro results and suggest that those compounds may be responsible of those activities. The predicted molecular parameters generated by OSIRIS show that the bioactive compounds would not present any risk of toxicity, except for the elemonic acid that could have a teratogenic effect. However, the presence of this compound in a natural mixture matrix reduces considerably its potential toxicity. This research manuscript is the first evaluation of Boswellia carterii resin dermo-cosmetic enzymatic activity, and highlights the valorization of Boswellia resin as a cosmeceutical using a combined computational/biological approach.

Author Contributions

Conceptualization, N.E.A. and F.E.; methodology, S.H. and N.E.A.; validation, N.E.A. and H.M.; formal analysis, J.M.R.; investigation, S.H., N.E.A. and H.M.; resources, N.E.A.; data curation, J.M.R.; writing—original draft preparation, S.H.; writing—review and editing, N.E.A. and J.M.R.; supervision, N.E.A.; project administration, N.E.A.; funding acquisition, N.E.A. and J.M.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Acknowledgments

This work is also based upon the work from COST Action 18101 SOURDOMICS—Sourdough biotechnology network towards novel, healthier and sustainable food and bioprocesses (https://sourdomics.com/; https://www.cost.eu/actions/CA18101/, accessed on 14 October 2022), where the author J.M.R. is the Chair and Grant Holder Scientific Representative, and the author N.E.A. is member, and is supported by COST (European Cooperation in Science and Technology) (https://www.cost.eu/, accessed on 14 October 2022). COST is a funding agency for research and innovation networks. Regarding the author J.M.R., he was also financially supported by LA/P/0045/2020 (ALiCE) and UIDB/00511/2020-UIDP/00511/2020 (LEPABE) funded by National funds through FCT/MCTES (PIDDAC).

Conflicts of Interest

The authors declare no conflict of interest.

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Cosmetics 09 00131 g001 550
Figure 1. General aspect of boswellia carterii tree (a); leaves (b); and resin (c).
Figure 1. General aspect of boswellia carterii tree (a); leaves (b); and resin (c).
Cosmetics 09 00131 g001
Cosmetics 09 00131 g002 550
Figure 2. Chemical structures of the main constituents selected as ligands for the in silico study.
Figure 2. Chemical structures of the main constituents selected as ligands for the in silico study.
Cosmetics 09 00131 g002
Cosmetics 09 00131 g003 550
Figure 3. Percentage of collagenase inhibition by resin extracts at 200 µg/mL. The letters a–c represents significant differences at p < 0.05 by Student’s t-test. Note: MeOH = methanol, Chex = n-hexane, and EtAc = ethyl acetate.
Figure 3. Percentage of collagenase inhibition by resin extracts at 200 µg/mL. The letters a–c represents significant differences at p < 0.05 by Student’s t-test. Note: MeOH = methanol, Chex = n-hexane, and EtAc = ethyl acetate.
Cosmetics 09 00131 g003
Cosmetics 09 00131 g004 550
Figure 4. Percentage of elastase inhibition by resin extracts at 200 µg/mL. The letters a–e represent significant differences at p < 0.05 by Student’s t-test. Note: MeOH = methanol, Chex = n-hexane, and EtAc = ethyl acetate.
Figure 4. Percentage of elastase inhibition by resin extracts at 200 µg/mL. The letters a–e represent significant differences at p < 0.05 by Student’s t-test. Note: MeOH = methanol, Chex = n-hexane, and EtAc = ethyl acetate.
Cosmetics 09 00131 g004
Cosmetics 09 00131 g005 550
Figure 5. 3D and 2D ligand–protein interactions at the collagenase active site of elemonic acid (PDB CID: 1CGL).
Figure 5. 3D and 2D ligand–protein interactions at the collagenase active site of elemonic acid (PDB CID: 1CGL).
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Cosmetics 09 00131 g006 550
Figure 6. 3D and 2D ligand–protein interactions at the elastase active site of acetyl 11-keto-beta-boswellic acid (PDB CID: 1BRU).
Figure 6. 3D and 2D ligand–protein interactions at the elastase active site of acetyl 11-keto-beta-boswellic acid (PDB CID: 1BRU).
Cosmetics 09 00131 g006
Table
Table 1. Virtual screening results of Boswellia carterii resin compounds against collagenase and elastase.
Table 1. Virtual screening results of Boswellia carterii resin compounds against collagenase and elastase.
N°CompoundPubchem (CID)Score (Kcal/mol)
CollagenaseElastase
111-keto-beta-boswellic acid6918114−9.5−5.6
2Acetyl 11-keto-beta-boswellic acid71463896−8.9−5.5
3Beta-boswellic acid168928−9.8−5.5
4Alpha-boswellic acid637234−10.4−5.2
5Acetyl-alpha-boswellic acid117072585−10−5
6Acetyl-beta-boswellic acid11386458−8.7−6.6
73-Oxotirucallic acid134693088−10.1−5.3
8Elemonic acid15559100−10.3−5.9
93-Beta-hydroxytirucallic acid441677−9.9−6.2
10Palmitic acid985−5.5−4.2
11Lupeol259846−10−5.7
12Incensole44583885−7.6−5.3
13Incensole acetate73755086−7.3−4.7
143-Alpha-hydroxytirucalla-7,24-dien-21-oic acid158143−10.2−6.4
15Lupeolic acid12111950−9.6−6.2
16Acetyl-9,11-dehydro-beta-boswellic acid44558899−10.6−5.3
179,11-Dehydro-beta-boswellic acid102509765−11−5.3
Table
Table 2. Docking scores of the Boswellia carterii resin selected compounds and amino acids involved in binding.
Table 2. Docking scores of the Boswellia carterii resin selected compounds and amino acids involved in binding.
N°CompoundCollagenaseElastase
Score (Kcal/mol)Involved Amino AcidsScore (Kcal/mol)Involved Amino Acids
111-Keto-beta-boswellic acid−9.6Asn180, His222, His228, Pro238−7.4His57, Leu99
2Acetyl 11-keto-beta-boswellic acid−9.2Asn180, His222, His228, Pro238−8.2Leu99, Trp172, Asn192, Ser195, Gly216
3Beta-boswellic acid−9.6Ala184, His228, Pro238−6.7Ser96, Leu99, Cys220
4Alpha-boswellic acid−10.0Ala184, His228, Pro238−6.4His40, His57, Asn192
5Acetyl-alpha-boswellic acid−9.6Leu181, Val215, His222, His228, Pro238−6.4His57, Gly216
6Acetyl-beta-boswellic acid−8.5Leu181, His218, His222, His228, Pro238−7.9Leu99, Trp172, Ser195, Gly216
8Elemonic acid−10.4Asn180, Leu181, Ala182, Val215, His218, His222, Pro238−7.4His57, Leu99, Asn192, Ser195, Val213, Cys220
10Palmitic acid−5.6Leu181, His183, Arg214, Val215, His218, His228, Pro238−4.2Leu99, Phe215
Table
Table 3. Molecular properties of resin compounds from Boswellia carterii.
Table 3. Molecular properties of resin compounds from Boswellia carterii.
N°CompoundToxicity Risk aBiodisponibility and Drug Score b
MUTTUMIRRTERPMCLPSDLDS
1Beta-boswellic acidCosmetics 09 00131 i001Cosmetics 09 00131 i002Cosmetics 09 00131 i003Cosmetics 09 00131 i004456.06.0−6.11−2.460.17
2Alpha-boswellic acidCosmetics 09 00131 i005Cosmetics 09 00131 i006Cosmetics 09 00131 i007Cosmetics 09 00131 i008456.06.06−6.13−2.030.18
3Acetyl-beta-boswellic acidCosmetics 09 00131 i009Cosmetics 09 00131 i010Cosmetics 09 00131 i011Cosmetics 09 00131 i012498.06.49−6.52−2.370.14
4Acetyl-alpha-boswellic acidCosmetics 09 00131 i013Cosmetics 09 00131 i014Cosmetics 09 00131 i015Cosmetics 09 00131 i016498.06.55−6.54−1.920.15
5Acetyl 11-keto-beta-boswellic acidCosmetics 09 00131 i017Cosmetics 09 00131 i018Cosmetics 09 00131 i019Cosmetics 09 00131 i020512.05.78−6.17−1.720.17
611-Keto-beta-boswellic acidCosmetics 09 00131 i021Cosmetics 09 00131 i022Cosmetics 09 00131 i023Cosmetics 09 00131 i024470.05.29−5.76−1.770.21
8Palmitic acidCosmetics 09 00131 i025Cosmetics 09 00131 i026Cosmetics 09 00131 i027Cosmetics 09 00131 i028256.06.06−4.24−25.220.09
10Elemonic acidCosmetics 09 00131 i029Cosmetics 09 00131 i030Cosmetics 09 00131 i031Cosmetics 09 00131 i032454.07.29−5.98−5.210.09
Green: non-toxic/Red: highly toxic/a MUT: mutagenic/TUM: tumorigenic/IRR: irritant/TER: teratogen/b PM: molecular weight/CLP: CLogP/S: solubility/DL: drug likeness/DS: drug score.
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Hourfane, S.; Mechqoq, H.; Errajouani, F.; Rocha, J.M.; El Aouad, N. In Vitro and In Silico Evaluations of Boswellia carterii Resin Dermocosmetic Activities. Cosmetics 2022, 9, 131. https://doi.org/10.3390/cosmetics9060131

AMA Style

Hourfane S, Mechqoq H, Errajouani F, Rocha JM, El Aouad N. In Vitro and In Silico Evaluations of Boswellia carterii Resin Dermocosmetic Activities. Cosmetics. 2022; 9(6):131. https://doi.org/10.3390/cosmetics9060131

Chicago/Turabian Style

Hourfane, Sohaib, Hicham Mechqoq, Fatima Errajouani, João Miguel Rocha, and Noureddine El Aouad. 2022. "In Vitro and In Silico Evaluations of Boswellia carterii Resin Dermocosmetic Activities" Cosmetics 9, no. 6: 131. https://doi.org/10.3390/cosmetics9060131

APA Style

Hourfane, S., Mechqoq, H., Errajouani, F., Rocha, J. M., & El Aouad, N. (2022). In Vitro and In Silico Evaluations of Boswellia carterii Resin Dermocosmetic Activities. Cosmetics, 9(6), 131. https://doi.org/10.3390/cosmetics9060131

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