
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12257-8
10.1016/j.heliyon.2024.e36226
e36226
Research Article
Valorization of hydro-distillate of fruit peels of Citrus paradisi macfad. Cultivar. Foster: Chemical profiling, antioxidant evaluation and in vitro and in silico enzyme inhibition studies
Sajid Rameen a
Abbas Zaheer b
Nazir Mamona c
Saleem Muhammad m.saleem@iub.edu.pk
a⁎⁎
Riaz Naheed a
Tousif Muhammad Imran Imran.tousif@ue.edu.pk
d⁎
Tauseef Saba e
Zengin Gokhan gokhanzengin@selcuk.edu.tr
f⁎⁎⁎
Uba Abdullahi Ibrahim g
Hussain Abdullah Ijaz h
Ali Muhammad Shaiq i
Hashem Abeer habeer@ksu.edu.sa
j
Almutairi Khalid F. almutairik@ksu.edu.sa
l
Avila-Quezada Graciela Dolores gdavila@uach.mx
k
Abd_Allah Elsayed Fathi eabdallah@ksu.edu.sa
l
a Institute of Chemistry, Baghdad-ul-Jadeed Campus, The Islamia University of Bahawalpur, 63100, Bahawalpur, Pakistan
b Department of Botany, Division of Science and Technology, University of Education Lahore, Pakistan
c Department of Chemistry, Government Sadiq College Women University Bahawalpur, 63100 Bahawalpur, Pakistan
d Department of Chemistry, Division of Science and Technology, University of Education Lahore, Pakistan
e Dr. Panjwani Center for Molecular Medicine and Drug Research., International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
f Department of Biology, Science Faculty, Selcuk University, 42130 Konya, Turkey
g Department of Molecular Biology and Genetics, Istanbul AREL University, 34537 Istanbul, Turkey
h Department of Chemistry, GC University Faisalabad, Pakistan
i International Center of Chemical and Biological Sciences, University of Karachi, 75270 Karachi, Pakistan
j Botany and Microbiology Department, College of Science, King Saud University, P.O. Box. 2460, Riyadh 11451, Saudi Arabia
k Facultad de Ciencias Agrotecnológicas, Universidad Autónoma de Chihuahua, 31350, Chihuahua, Chihuahua, Mexico
l Plant Production Department, College of Food and Agricultural Sciences, King Saud University, P.O. Box. 2460, Riyadh 11451, Saudi Arabia
⁎ Corresponding author. Imran.tousif@ue.edu.pk
⁎⁎ Corresponding author. m.saleem@iub.edu.pk
⁎⁎⁎ Corresponding author. gokhanzengin@selcuk.edu.tr
21 8 2024
15 9 2024
21 8 2024
10 17 e3622612 12 2023
11 8 2024
12 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
The major commercial crops in Pakistan are citrus fruit trees, which are farmed extensively and serve as the country's principal source of foreign exchange. A local citrus plant, Citrus paradisi, variety Foster is famous for its valuable fruit and fruit juice, however, tons of peels of this fruit are thrown as waste, which otherwise can be utilized in formulating nutraceutical and cosmetics. In the present study, essential oil of fruit peels was obtained through hydro-distillation, which was then analyzed through GC-MS analysis and studied for its antioxidant and enzyme inhibition potential. GCMS analysis revealed the presence of several components; major were found to be limonene, α-terpineol, caryophyllene, δ-amorphene, elemol, γ-eudesoml, nootkatone and di-isooctyl phthalate. Although, the oil showed weak free radical inhibition, it was potentially active in CUPRAC, FRAP, phosphomolybdenum and metal chelating antioxidant assays. The oil also exhibited anti-glucosidase, anti-amylase activities and also exhibited potent inhibition of the enzyme tyrosinase, which makes it strong candidate for nutraceuticals and skin care products. The docking studies also substantiate our results and caryophyllene, γ-eudesoml and nootkatone showed good binding affinity α-glucosidase and α-amylase and all tested compounds showed the higher binding affinity towards the enzyme tyrosinase.

Keywords

Citrus paradisi cultivar foster
Essential oil
GC-MS analysis
Antioxidant
Enzyme inhibition
In silico studies
==== Body
pmc1 Introduction

The Genus Citrus of the plant family Rutaceae, is one among the main fruit crops in tropical, subtropical and temperate regions around the globe [1,2]. Striking feature of the citrus plants is that, hybrid varieties are easily be produced by cross breeding among different species [3], which results into increased production of citrus fruits with various fragrance, flavor and types. The most common citrus fruits are oranges, grapefruits, mandarins, lemons and limes, which are popular due to their flavors, nutritional and health benefits and thus are the main industrialized crops all over the world [2,4]. Recent statistical analysis revealed that the global business of citrus was estimated as USD 7601.7 million in 2023, which is predicted to increase 10437.1 million in 2030 [5]. Citrus plants are aromatic due to their volatile oil contents [6], besides they produce bioactive secondary metabolites that can combat against disease and promote human health. Citrus fruits are rich in vitamin C, folic acid, potassium and pectin, in fact vitamin C contents are higher in fruit peels as compared to juice [7,8].

Several studies have proved that citrus peels and their extracts exhibit potent pharmacological activities and health benefits due to their bioactive contents and antioxidant properties [9]. In addition to antioxidant phenolics and flavonoids, citrus peels are rich source of volatile oils with higher limonene and vitamin C contents. Published data shows that appropriate intake of antioxidants improves the immune system and thus reduces the severity and duration of colds, flus, and other viruses [10]; it makes citrus fruits a precious food crop.

Several studies have been conducted on extraction, identification and bioactivities of essential oils of citrus fruit peels. For example peel essential oil of C. aurantifolia has been reported to possess in vivo cholesterol lowering properties [11]. Matsuura et al. studied tyrosinase inhibitory activities of several citrus fruit peel essential oils and found significant potential associated to these oils [12]. Sweet orange, bergamot and lemon fruit peel essential oils showed significant larvicidal activity [13]. Lemon fruit peel essential oil has also been reported to exhibit antioxidant and antimicrobial activities [14]. Orange fruit peel essential oil inhibited the growth of various food spoiling and other pathogenic bacteria [[15], [16], [17]]. Hydro-distilled essential oils of fruit peels of mandarin were found antioxidant which also showed antimicrobial activities against Leuconostoc mesenteroides, Escherichia coli and Lactobacillus plantarum [18]. Another report describes that essential oil of fruit peel of C. reticulate exhibit antibacterial and wound healing properties [19]. DPPH* inhibitory activities of fruit peel essential oils of C. reticulate, C. paradisi and C. lemon have been reported along with antimicrobial activities against Bacillus subtilis, Penicillium chrysogenum, Fusarium moniliforme, Aspergillus niger, Aspergillus flavus, Saccharomyces cerevisiae) and pathogenic microorganisms (Escherichia coli, Salmonella abony, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans), and thus essential oils of these fruits can be used in bio-preservation strategies [20,21]. Interestingly, citrus peel essential oils also increased the shelf-life of strawberries and thus played important role in food preservation [22].

Citrus paradisi (common name grapefruit) is a hybrid of two Citrus species; C. sinensis and C. maxima or Citrus grandis Osbeck [23,24]. It is native to island of Barbados in West Indies, but also widely grown in different parts of Asia, America, Israel, Cuba, Argentina, and South Africa [25,26]. Two common varieties of grapefruit are available depending upon the color of the pulp; the white and redblush or foster pink.

In addition to its importance as food crop, C. paradisi is medicinally very important natural source. Its juice decreases diastolic arterial pressure and systolic arterial pressure both in normotensive and hypertensive subjects [27]. It is also effective in gastric problems and exhibit antiulcer properties due its antioxidant flavonoids. Its flavonoids are also reported to possess antibacterial, anti-helicobacter pylori activity showed cytoprotection against injury [28,29]. Grapefruit peel essential oils exhibited antibacterial properties against Salmonella parathypi, Vibrio vulnificus and Seratialique faciens [30], and several other pathogenic bacteria and fungi [31]. Some studies revealed that peels of grapefruit are used in controlling diabetes and hypertension [32]. Grapefruit essential oil also exerted inhibitory effects on the proliferation of HepG2 liver cancer cells and HCT116 colon cancer cells [33].

Although citrus fruit plants are the major commercial crops in Pakistan which are grown at wide area and the export valued about 166 million USD [34], the research on local variety Foster of C. paradisi is only scanty, which otherwise may provide a potential source to develop nutraceuticals and cosmetic ingredients. Despite of being a tremendous source of nutrients, chemicals, minerals and its cholesterol lowering property, yet its peels are thought to be as waste in local market. Further, fruit peels or its essential oils are not much explored locally for its medicinal values. Fewer studies disclosed the yield of essential oil from C. paradisi is ∼3.9 % comprising of aliphatic hydrocarbons, alcohols, aldehydes, ketones, esters and terpenoids [35]. Limonene the main components of various oils have anti-proliferative action. Cell proliferation was affected by limonene in a biphasic manner; an increase in peroxidase and catalase activity was linked to a reduction in H2O2 levels. Additionally, limonene shielded the cells against the exogenous injection of H2O2-induced oxidative damage [36]. Furthermore, the synthesis of cytokines is modulated by limonene and is able to alter signalling pathways associated with a number of illnesses [37].

In the present study, hydro-distilled essential oil of locally grown grapefruit peels was analyzed through GC-MS and was evaluated for its free radical inhibition (DPPH*, ABTS*+), metal reducing (FRAP, CUPRAC), metal chelating and enzyme (AChE, BChE, tyrosinase, α-glucosidase and α-amylase) inhibition activities.

2 Experimental

2.1 Plant material

The fresh fruits of C. paradisi (Grapefruit-Foster) were purchased from local market in Bahawalpur, which were authenticated by Dr. Farrukh Nisar, plant taxonomist in the department of Biochemistry, Cholistan University Bahawalpur, Pakistan. The fruits were peeled and pulp and inner peel skin was fully removed from the peels.

2.2 Extraction of the essential oil

The peels (2.0 kg) of C. paradisi were cut into small pieces and were subjected to hydro-distillation for approximately 3 h. A recirculating chiller (0 °C) was used for condensation of distilled vapors. The distillate obtained were separated by separating funnel and moisture was removed from the pale yellow layer of essential oil by adding anhydrous sodium sulphate and then stored in vials at 4 °C for further analysis and biological studies.

2.3 GC-MS analysis

A GC TRACE-1300 gas chromatograph connected to an MS, ISQ, and auto sampler AI-1310 was used to analyze the essential oil. The instrument used was a capillary column TR-35 MS GC Column 30mx.25mmIDx.25μm. The analysis used an injector temperature of 250 °C, and the column temperature was first programmed to be 50 °C for 5 min, then to be 5 °C/min to 140 °C, then 7 °C/min to 275 °C, and finally to be held for 10 min. The temperature of the transfer line was 250 °C, and the temperature of the ion source was 200 °C. The sample delay period started at 3.5 min. Split less injection was utilized, and the carrier gas used was helium 99.9992 % with a gas flow rate of 1.5 ml/min. Mass spectra were obtained after a 1-μl volume was injected and 70 electron volts of ionization energy were used. The NIST (National Institute of Standards and Technology) Mass spectral search and library system was utilized by the Xcalibur software data system to analyses the obtained mass spectra. The NIST/EPA/NIH main library was the library that was used to match data.

2.4 Antioxidant activities assays

The essential oil's antioxidant activity was estimated by following pre-established protocols (For details see supplementary file). For FRAP, ABTS*+, DPPH*, CUPRAC, and total antioxidant capacity, trolox equivalent was utilized as the standard; for metal chelating assays, ethylene diamine tetraacetic acid (EDTA) was the standard [38,39].

2.5 Enzyme inhibition assays

The α-amylase, α-glucosidase, BChE, tyrosinase, and AChE enzyme inhibitory assays were conducted using previously published methods. The inhibitory activity of α-amylase and α-glucosidase was measured using acarbose (mmol ACAE/g extract) as the standard, the inhibitory activity of AChE and BChE was measured using galantamine (mg GALAE/g extract), and the inhibitory activity of tyrosinase was measured using kojic acid (mmol KAE/g extract) [40,41]. For antioxidant and enzyme inhibitory assays, the sample solutions were carefully formulated in ethanol at a concentration of 2 mg/mL. All chemicals were freshly prepared, with special attention to keeping them in an ice bath for the upcoming use (For details see supplementary file).

2.6 Docking analysis

Molecular docking studies can be very helpful for learning about possible drugs' selectivity and steric properties, which can be used to anticipate their locations of binding for potential inhibition. and improvement of potential therapeutic drugs [42]. The 3D sdf structures of five compounds were retrieved from PubChem [43]. The structures were converted to pdb format and energy was minimized prior to docking through Chem3D Ultra 16.0. the three protein structures were retrieved from the Protein Data Bank (PDB) database [44]. In order to identify the potential of drug-target interaction, Autodock software (version 4.2) was used to perform molecular docking on five compounds with α-amylase, α-glucosidase and tyrosinase using the Lamarckian genetic method [45]. The receptor proteins remained rigid, while the ligands were made flexible in order to move and investigate the most likely binding postures. The docking was performed in a similar fashion reported previously [46]. The resulting binding poses were visualized using Discovery Studio Visualizer 3.5 [47]. The interactions were investigated in terms of binding energy (Kcal/mol), Ki (Inhibition constant) value (M), and the hydrogen bonds formed and interaction patterns observed within residues of protein and ligand.

3 Results and discussion

Pale yellow dried hydro-distilled essential oil (HDEO) of fruit peels of Citrus paradisi cultivar Foster was obtained in 1.18 % (w/w) yield, which exhibited pleasant citrus smell. A complex chromatogram of HDEO was obtained as result of gas chromatography (Fig. 1), however, 12 components could be identified through their retention time and fragmentation patterns in their respective mass spectra. The identified metabolites of HDEO along with their retention time and percentage area are shown in Table 1. 97.09 % of the total HDEO comprised of only 08 metabolites (Table 1), while others were found in trace amounts. Most of the constituents of HDEO were found as monoterpene hydrocarbons, aliphatic aldehydes, sesquiterpenes, esters, acids, alcohols, ketones, and other oxygenated compounds with limonene (53.81 %) and nootkatone (22.12 %) as major components. Okunowo et al. also published a report on hydro-distillation of grapefruit peel essential oil with limonene as major component as reported by adebisi et al. [48]; however, they did not observe nootkatone [31], while other reports revealed nootkatone as one among the major components of C. paradisi fruit peel essential oil [21,23,[49], [50], [51]] with varying % age.Fig. 1 Gas chromatogram of Citrus paradisi cultivar Foster peel essential oil (HDEO).

Fig. 1

Table 1 Constituents of Citrus paradisi cultivar Foster fruit peel hydro-distilled essential oil (HDEO).

Table 1No.	RT(min)	RI	Mass fragments (m/z)	Molecular Formula	Compound	Mode of identification	Peak area (%)	
1	13.33	1029	136, 121, 107, 93, 79, 68, 53, 41	C10H16	Limonene	RT, RI,MS	53.81	
2	17.67	1189	154, 121, 93, 81, 59, 43	C10H18O	α-Terpineol	RT, RI,MS	Tr	
3	17.89	1497	112, 95, 82, 68, 57, 43	C10H20O	Decanal	RT, RI,MS	Tr	
4	19.46	–	111, 97, 83, 70, 69, 55, 43, 41	C10H22O	1-Decanol	RT, MS	Tr	
5	21.50	–	172, 129, 83, 73, 69, 60, 56, 43	C10H20O2	n-Decanoic acid	RT, MS	Tr	
6	23.29	1583	189, 175, 161, 147, 133, 120, 105, 91, 79, 69, 55, 41	C15H24	Caryophyllene	RT, RI,MS	2.37	
7	24.88	–	206, 191, 175, 163, 147, 128, 119, 107, 91, 77, 60, 57, 44, 41	C14H22O	2,4-Di-tert butyl phenol	RT, MS	Tr	
8	25.38	1442	204, 189, 161, 143, 134, 129, 119, 105, 91, 77, 67, 55, 41	C15H24	δ-Amorphene	RT, RI,MS	1.45	
9	25.99	1550	189, 161, 147,134, 119, 107, 93, 79, 67, 59, 55, 43	C15H26O	Elemol	RT, RI,MS	2.67	
10	28.40	–	222, 204, 189, 175, 161, 147, 133, 119, 107, 91, 79, 67, 59, 55, 41	C15H26O	γ-Eudesoml	RT, MS	5.33	
11	35.79	2563	218, 203, 190, 175, 161, 147, 133, 121, 105, 91, 79, 67, 53, 51	C15H22O	Nootkatone	RT, RI,MS	22.12	
12	64.46	–	279, 207, 190, 167, 149, 113, 83, 71, 57, 43	C24H38O4	Di-iso-octyl phthalate	RT, MS	7.39	
	Total identified %		97.09	
	Varies		–	–	Others		2.91	
RT = Retention time (compounds were listed in order of elution from an HP-5MS column); RI = Retention indices, Retention indices relative to C9–C24 n-alkanes on the HP-5MS column; Tr = Trace amount t = trace (<0.05 %); MS = identification based on comparison of mass.

Additional substances found in HDEO included aliphatic aldehydes like decanal, alcohols like α-terpineol and 1-decanol, and trace amounts of acids like n-decanoic acid. Prominent components included caryophyllene (2.37 %), δ-amorphene (1.45 %), di-iso-octyl phthalate (7.39 %), elemol (2.67 %), γ-eudesmol (5.33 %), and 2,4-DTBP (2,4-di-tert-butylphenol) (1.95 %). This source has yielded the first report of 2,4-di-tert-butylphenol in the current study. When comparing our sample of C. paradisi to those published in the literature by Okunowo et al., the percentages of caryophyllene and phthalate were higher, mounting up to 1.88 % and 0.54 %, respectively [31]. Previous studies have noted that during different developmental stages of fruit ripening, the content and composite function of oil can even vary within the same genus [16]. Using a similar method, Karioti et al. reported that the main compounds in the Nigerian mandarin leaf oil were γ-terpinene and linalool, while limonene was the main constituent in the peel oils of both grapefruit and Nigerian mandarin [52]. Additionally, literature reports that the essential oils of C. paradisi had a higher percentage of the limonene component [53], and consequently, the published data supported our findings. In contrast to its previously studied leaf oil (11.37 %) from Nigeria, the percentage of limonene component in the peel oil of C. paradisi was higher (53.881 %) in the recently investigated peel oil [52]. and this variation must be because of environmental changes.

3.1 Antioxidant activities of the HDEO

Fruit peel hydro-distilled essential oil (HDEO) of C. paradisi was investigated for its antioxidant activities in various assays including DPPH* and ABTS*+ free radical scavenging, metal reducing, metal chelating and Phosphomolybdenum assays. Against DPPH* free radical, HDEO was found inactive, however, it showed mild (3.98 ± 0.36 mgTE/g extract) scavenging activity against ABTS*+. Literature reports revealed that other citrus fruit essential oils exhibited free radical scavenging activities [[54], [55], [56], [57]], however, grapefruit essential oil is reported almost inactive against DPPH* free radical [58]. Therefore, literature reports substantiated our results, while the activity difference could be attributed to the absence of phenolic components in HDEO. In cupric (CUPRAC) and ferric (FRAP) reducing capacity assays, HDEO exhibited significant activity with the values of 45.15 ± 1.59 and 24.33 ± 0.18 mgTE/g extract, respectively (Table 2). Gargouri et al. have reported similar results where 60 % ferric reducing power of C. paradisi essential oil was observed, whereas, in another study, the essential oils of C. sinensis [59,60] and C. limon [61] have shown mild cupric reducing power. Since no single component of HDEO has been reported in literature to show metal reducing capacity, the activity of HDEO could be attributed to synergic effect of its various components. In Phosphomolybdenum assay, a significant total antioxidant capacity has been observed (0.73 ± 0.08 mmolTE/g) for HDEO which is fully supported by the literature values [59,62]. Iron chelating activity of HDEO was also measured, where it showed significant chelating value of 1.15 ± 0.10 mg EDTAE/g extract (Table 2), which has also been supported by the previously published data [63,64]. According to a recent study, the essential oil extracted from the peel of Citrus reticulata Blanco demonstrated potent antioxidant properties, including the ability to scavenge DPPH* and ABTS*+ radicals, as well as H2O2 and ferric reducing antioxidant capacity and prevent lipid peroxidation [65]. In another investigation, the citrus limetta risso's limonene-rich essential oil demonstrated its ability to quench radicals using DPPH radical scavenging (11.35 ± 0.51 μg/mL) and ABTS scavenging (10.36 ± 0.55 μg/mL) [66].Table 2 Antioxidant and enzyme inhibitory activities of the of Citrus paradisi peels hydro-distilled essential oil (HDEO).

Table 2Sample code	Antioxidant activity	
HDEO	Radical scavenging assays	Reducing power assays	Total antioxidant capacity	Ferrous ion chelation	
DPPHa (mgTE/g extract)a	ABTSa+ (mgTE/g extract)a	CUPRAC (mgTE/g extract)a	FRAP (mgTE/g extract)a	Phosphomolybdenum (mmolTE/g extract)a	Metal chelating (mgEDTAE/g extract)a	
na	3.98 ± 0.36	45.15 ± 1.59	24.33 ± 0.18	0.73 ± 0.08	1.15 ± 0.10	
Enzyme inhibitory studies	
AChE (mg GALAE/g extract)a	BChE (mg GALAE/g extract)a	Tyrosinase (mgKAE/g extract)a	α-Amylase (mmolACAE/g extract)a	α-Glucosidase (mmolACAE/g extract)a	
4.31 ± 0.00	6.25 ± 0.69	53.19 ± 0.40	0.55 ± 0.02	1.78 ± 0.01	
a Values expressed are means ± S.D. of three parallel measurements. HDEO: Hydro-distilled essential oil of fruit peels of Citrus paradisi var. Foster. TE: Trolox equivalent; EDTAE: EDTA equivalent. AChE: Acetylcholinesterase; BChE: Butyrylcholinesterase; GALAE: Galatamineequivalent; KAE: Kojic acid equivalent; ACAE: Acarbose equivalent; na: not active.

3.2 Enzyme inhibition activities of the HDEO

Fruit peel hydro-distilled essential oil (HDEO) of C. paradisi was also investigated for its enzyme inhibition potential against AChE, BChE, tyrosinase, α-amylase and α-glucosidase. It was weakly active against AChE and BChE, but showed potent tyrosinase inhibition with the value of 53.19 ± 0.40 mgKAE/g extract (Table 2). Literature reports also endorsed our results, since citrus essential oils have shown tyrosinase inhibitory activity [12,[67], [68], [69]]. Recently, Yang et al. have studied fruit peel essential oil of several citrus spices and found all of them as anti-melanogenesis, and suggested their use in cosmetics and pharmaceutics against skin hyperpigmentation [70]. It is also reported that limonene and terpineol are the most active component in citrus essential oils. In another report, da Silva et al. disclosed that eudesmol and caryophyllene are potential inhibitors of the enzyme tyrosinase, which they confirmed trough in vitro and in silico studies [71]. GCMS analysis of HDEO disclosed the presence of limonene as main component (∼54 %) as reported previously [72], along with eudesmol, caryophyllene, nootkatone as major ingredients and several other important components thus substantiate the worth of HDEO as potential ingredient in skin care products.

HDEO also exhibited moderate antidiabetic properties, since it exerted significant inhibitory activity against α-glucosidase (1.78 ± 0.01 mmolACAE/g extract) and weak activity (0.55 ± 0.02 mmolACAE/g extract) against α-amylase. Previously Dang et al. also studied α-glucosidase inhibitory activity of citrus fruit peel essential oils and found notable antidiabetic properties [73]. Oboh et al. also reported antidiabetic potential of essential oils from orange and lemon fruit peels [74]. In published data, α-glucosidase activities of citrus fruit peel essential oils are attributed to its terpene contents, since they exert blood glucose lowering effects [[75], [76], [77]] Guo et al. studied α-glucosidase inhibitory activities of a nootkatone derivative in C. paradisi fruit peel essential oil, and found to show antidiabetic properties [78]. The HDEO is also rich in monoterpenes and thus the α-glucosidase and α-amylase inhibitory activities are attributed to its monoterpene contents.

3.3 Post dock analysis

The molecular interaction that transports the ligand from the protein surface to the active site indicates the significant affinities for the target proteins that were identified in docking studies. γ-Eudesmol, a sesquiterpenoid compound, was consistently shown to have lower binding energies for all three enzymes and have greater affinity towards α-amylase while nootkatone and caryophyllene showed lower binding affinity along with γ-Eudesmol towards α-glucosidase and tyrosinase respectively described in Table 3, Table 4. The post dock analysis revealed that γ-Eudesmol and nootkatone showed binding energies −8.70 kcal/mol and −7.20 kcal/mol for α-glucosidase, which is comparable to the binding affinity of acarbose −9.62 kcal/mol. The interaction patterns suggested that both compounds form a number of hydrophobic interactions while it fail to form any type of hydrogen bonds (Fig. 2 A-B). The interactions patterns suggest that as both compounds fail to depict hydrogen bonds, may be one of the reason to have lesser binding affinity than acarbose. Similar trend was also observed for α-amylase where acarbose formed nine hydrogen bond with an additional Pi-donor hydrogen bond contributing towards an overall binding affinity of −9.58 kcal/mol. The nootkatone formed two hydrogen bonds along with alkyl and pi-alkyl interactions and contributed towards binding affinity of −6.58 kcal/mol. The γ-Eudesmol formed same interactions as nootkatone and contributed binding affinity of −6.17 kcal/mol (Fig. 2C–D). The five compounds showed a significant binding affinity towards tyrosinase almost equal to kojic acid. The caryophyllene, γ-Eudesmol and nootkatone showed better binding affinity than rest of the two compounds. Although both compounds caryophyllene, and γ-Eudesmol formed only hydrophobic interactions but the number of interactions formed by these two compounds were enough to raise their binding affinity to −6.05 kcal/mol and −5.85 kcal/mol respectively (Fig. 3A–B). Table 2 summarizes the binding interaction patterns of compounds with binding affinity along with reference compounds.Table 3 Binding free energy and inhibition constants of compounds α-glucosidase, α-amylase, and Tyrosinase.

Table 3Compounds	α-glucosidase	α-amylase	Tyrosinase	
Free Energy of Binding kcal/mol	Estimated Inhibition Constant	Free Energy of Binding kcal/mol	Estimated Inhibition Constant	Free Energy of Binding kcal/mol	Estimated Inhibition Constant	
aReference Compound	−9.62	88.89 nM	−9.58	95.58 nM	−4.07	1.04 mM	
Caryophyllene	−6.99	7.53 μM	−5.83	53.42 μM	−6.05	36.70 μM	
γ-Eudesmol	−8.70	417.58 nM	−6.17	30.16 μM	−5.85	51.85 μM	
Limonene	−6.12	32.53 μM	−4.14	917.59 μM	−4.32	683.21 μM	
Nootkatone	−7.20	5.32 μM	−6.58	14.92 μM	−5.67	69.32 μM	
Terpineol	−6.04	37.26 μM	−4.56	452.98 μM	−4.66	386.57 μM	
δ-Amorphene	−7.71	2.22 μM	−6.47	18.21 μM	−7.07	6.54 μM	
Elemol	−6.96	7.90 μM	−5.75	61.25 μM	−6.14	31.59 μM	
Di-iso-octyl phthalate	−6.59	14.81 μM	−5.27	137.41 μM	−4.72	347.40 μM	
a For α-glucosidase and α-amylase, acarbose is used as reference compound. While kojic acid is used as reference for Tyrosinase.

Table 4 Details of interaction patterns of docked complex for Selected compounds.

Table 4Ligands	Bond Category	Bond Distance	Bond type	Interactions	
Residue Name and Groups	From Chemistry	Residue Name and Groups	To Chemistry	
Interaction Patterns for α–glucosidase	
Acarbose	Hydrogen Bond	2.77725	Conventional Hydrogen Bond	A:ARG629:HN	H-Donor	D:GLC1:O2	H-Acceptor	
2.80785	A:ASP630:HN	D:GLC1:O2	
2.79736	D:GLC1:O6	D:AC13:O5	
3.29623	D:GLC2:O3	A:ASP568:OD1	
3.3492	D:AC13:O3	D:AC13:O6B	
3.37223	D:AC13:N4A	A:ASP232:O	
2.80319	D:AC13:O2B	A:ASP232:OD2	
Hydrogen Bond	3.35883	Pi-Donor Hydrogen Bond	D:AC13:O3B	H-Donor	A:PHE476	Pi-Orbitals	
γ-Eudesoml	Hydrophobic	5.49239	Alkyl	LIG0:C	Alkyl	A:MET470	Alkyl	
4.8416	LIG0:C	A:MET470	
Hydrophobic	5.09268	Pi-Alkyl	A:TRP329	Pi-Orbitals	LIG0	Alkyl	
5.31521	A:TRP432	LIG0:C	
4.34795	A:TRP432	LIG0:C	
4.23027	A:TRP432	LIG0:C	
5.20404	A:TRP432	LIG0	
4.43833	A:TRP432	LIG0:C	
5.10786	A:TRP467	LIG0	
4.80578	A:TRP565	LIG0:C	
5.24264	A:PHE601	LIG0	
4.88464	A:PHE601	LIG0	
5.01613	A:HIS626	LIG0	
Nootkatone	Hydrophobic	5.48322	Alkyl	A:MET470	Alkyl	LIG0	Alkyl	
4.32919	LIG0:C	A:ILE358	
Hydrophobic	4.1586	Pi-Alkyl	A:TRP329	Pi-Orbitals	LIG0:C	Alkyl	
3.74465	A:TRP329	LIG0:C	
5.33381	A:TRP329	LIG0	
4.45396	A:TRP329	LIG0:C	
4.46493	A:TRP329	LIG0:C	
4.01912	A:TRP329	LIG0:C	
4.98923	A:TRP432	LIG0:C	
4.95507	A:TRP432	LIG0	
5.16287	A:TRP432	LIG0:C	
5.06696	A:TRP432	LIG0:C	
4.54004	A:PHE601	LIG0:C	
4.5383	A:PHE601	LIG0:C	
4.6795	A:HIS626	LIG0:C	
Interaction Patterns for α–amylase	
Acarbose	Hydrogen Bond	2.00279	Conventional Hydrogen Bond	A:GLY167:HN	H-Donor	A:ABC479:O3H	H-Acceptor	
2.99957	A:ABC479:O3G	A:ABC479:O1L	
2.6108	A:ABC479:O4G	A:ABC479:O3L	
3.36955	A:ABC479:O2H	A:ABC479:O3I	
2.74339	A:ABC479:O3I	A:ILE152:O	
2.97893	A:ABC479:O2I	A:ILE152:O	
3.31839	A:ABC479:O2I	A:GLN153:O	
3.11009	A:ABC479:O2L	A:GLU230:OE2	
2.80189	A:ABC479:O6I	A:ABC479:O6H	
Hydrogen Bond	3.20313	Pi-Donor Hydrogen Bond	A:ABC479:O3K	H-Donor	A:TYR155	Pi-Orbitals	
γ-Eudesoml	Hydrogen Bond	2.04215	Conventional Hydrogen Bond	LIG0:H	H-Donor	A:ASP206:OD2	H-Acceptor	
Hydrophobic	4.23028	Alkyl	LIG0:C	Alkyl	A:LEU166	Alkyl	
5.26636	LIG0:C	A:LEU173	
3.9084	LIG0:C	A:LEU173	
Hydrophobic	5.14759	Pi-Alkyl	A:HIS80	Pi-Orbitals	LIG0	Alkyl	
5.42681	A:HIS80	LIG0	
4.48178	A:TYR82	LIG0:C	
5.46758	A:TYR82	LIG0	
4.87703	A:TRP83	LIG0	
4.40036	A:TRP83	LIG0	
5.21443	A:TRP83	LIG0:C	
4.58881	A:TRP83	LIG0	
4.29897	A:HIS122	LIG0:C	
Nootkatone	Hydrogen Bond	1.9922	Conventional Hydrogen Bond	A:ARG344:HH12	H-Donor	LIG0:O	H-Acceptor	
2.64594	A:ARG344:HH22	LIG0:O	
Hydrophobic	4.99489	Alkyl	LIG0:C	Alkyl	A:LEU173	Alkyl	
3.68782	LIG0:C	A:VAL171	
3.78241	LIG0:C	A:LEU173	
4.43959	LIG0:C	A:VAL171	
Hydrophobic	4.60171	Pi-Alkyl	A:TYR75	Pi-Orbitals	LIG0:C	Alkyl	
5.34175	A:TYR82	LIG0:C	
4.98375	A:TRP83	LIG0	
4.64208	A:TRP83	LIG0:C	
4.33118	A:TRP83	LIG0:C	
5.26202	A:TRP83	LIG0	
4.95911	A:TRP83	LIG0:C	
5.37695	A:HIS122	LIG0:C	
Interaction Patterns for Tyrosinase	
Kojic Acid	Hydrogen Bond	2.17753	Conventional Hydrogen Bond	A:ASN205:HD22	H-Donor	A:KOJ1351:O6	H-Acceptor	
3.20502	A:KOJ1351:O2	A:ASN205:O	
2.83555	A:KOJ1351:O6	A:GLU195:OE1	
Hydrogen Bond	3.31649	Carbon Hydrogen Bond	A:HIS204:CE1	H-Donor	A:KOJ1351:O5	H-Acceptor	
3.70276	A:HIS204:CE1	A:KOJ1351:O6	
δ-Amorphene	Hydrophobic	3.68229	Pi-Sigma	:UNN0:C	C–H	A:HIS208	Pi-Orbitals	
Hydrophobic	4.66568	Alkyl	A:VAL218	Alkyl	:UNN0	Alkyl	
3.37349	A:ALA221	:UNN0:C	
4.76268	:UNN0:C	A:MET61	
5.27111	:UNN0:C	A:VAL218	
4.8625	:UNN0:C	A:VAL218	
4.41771	:UNN0:C	A:ARG209	
Hydrophobic	3.93042	Pi-Alkyl	A:HIS60	Pi-Orbitals	:UNN0:C	Alkyl	
5.46735	A:PHE197	:UNN0:C	
5.20058	A:HIS204	:UNN0	
3.55883	A:HIS208	:UNN0	
Elemol	Hydrophobic	5.30146	Alkyl	A:ARG209	Alkyl	:UNN0	Alkyl	
3.74544	A:ALA221	:UNN0:C	
3.89686	:UNN0:C	A:PRO201	
4.05458	:UNN0:C	A:ARG209	
4.16395	:UNN0:C	A:VAL218	
5.08068	:UNN0:C	A:MET61	
4.7168	:UNN0:C	A:VAL218	
4.5477	:UNN0:C	A:VAL218	
4.58365	:UNN0:C	A:VAL218	
Hydrophobic	4.81841	Pi-Alkyl	A:HIS60	Pi-Orbitals	:UNN0:C	Alkyl	
4.12758	A:HIS60	:UNN0:C	
4.3964	A:PHE197	:UNN0:C	
4.68953	A:HIS204	:UNN0:C	
5.43544	A:HIS208	:UNN0	
4.66318	A:HIS208	:UNN0:C	
3.68856	A:HIS208	:UNN0:C	

Fig. 2 Binding interactions of compounds with α-glucosidase and α-amylase; A). Interaction patterns of γ-Eudesmol with α-glucosidase; B). Interaction patterns of Nootkatone with α-glucosidase; C). Interaction patterns of γ-Eudesmol with α-amylase; D). Interaction patterns of Nootkatone with α-amylase.

Fig. 2

Fig. 3 Binding interactions of compounds with tyrosinase; A). Interaction patterns of δ-Amorphene with tyrosinase; B). Interaction patterns of Elemol with tyrosinase.

Fig. 3

4 Conclusion

C. paradisi var. Foster fruit peel hydro-distilled essential oil (HDEO) comprised mostly of limonene, nootkatone, γ-Eudesoml and caryophyllene. HDEO also exhibited moderate to good antioxidant and antidiabetic activities in various assays, which make this oil important component in several skin and health care products or in nutraceuticals. Another worthy feature of HDEO is the inhibition of tyrosinase enzyme. Since limonene, terpineol, eudesmol and caryophyllene have already shown tyrosinase inhibitory or anti-melanogenesis properties, the HDEO rich in these components can be a potential ingredient in skin care products for hyperpigmentation and melanogenesis. Further docking studies confirm that caryophyllene, γ-eudesoml, and nootkatone bind well to α-glucosidase and α-amylase, but all investigated compounds had a greater binding affinity for tyrosinase. In local market, after the extraction of juice, the peels of C. paradisi are thrown as waste, therefore, it is suggested that essential oil of C. paradisi fruit peels if added to skin care products or other formulations may not only act as fragrance but also are potential active ingredient; even addition of dried powdered peels of C. paradisi var. Foster to skin cleansing products will increase their anti-hyperpigmentation and anti-melanogenesis effects and may reduce to decrease the cost of the products. Browning of stored food is a big problem in food industry, whereas, citrus peel essential oils increase the shelf-life of certain fruits, and thus played important role in food preservation. Keeping in view these facts and anti-tyrosinase activity of HDEO, it is suggested that essential oil of fruit peels of C. paradisi var. Foster can also be used as food preservative.

Funding

The authors would like to extend their sincere appreciation to the Researchers Supporting Project Number (RSP2024R134), 10.13039/501100002383 King Saud University , Riyadh, Saudi Arabia.

CRediT authorship contribution statement

Rameen Sajid: Investigation. Zaheer Abbas: Writing – review & editing. Mamona Nazir: Formal analysis. Muhammad Saleem: Writing – original draft, Supervision, Conceptualization. Naheed Riaz: Supervision, Investigation. Muhammad Imran Tousif: Writing – review & editing, Writing – original draft, Investigation, Formal analysis. Saba Tauseef: Writing – original draft, Formal analysis. Gokhan Zengin: Writing – review & editing, Writing – original draft, Investigation, Formal analysis. Abdullahi Ibrahim Uba: Investigation, Formal analysis. Abdullah Ijaz Hussain: Investigation, Formal analysis. Muhammad Shaiq Ali: Investigation, Formal analysis. Abeer Hashem: Writing – review & editing, Software, Funding acquisition. Khalid F.Almutairi: writing- review & editing, funding acquistion. Graciela Dolores Avila-Quezada: Avila-Quezada, Funding acquisition, Formal analysis. Elsayed Fathi Abd_Allah: Funding acquisition, Formal analysis.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following is/are the supplementary data to this article.Multimedia component 1

Multimedia component 1

Acknowledgement

The authors would like to extend their sincere appreciation to the Researchers Supporting Project Number (RSP2024R134 ), 10.13039/501100002383 King Saud University , Riyadh, Saudi Arabia.

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36226.
==== Refs
References

1 Ramírez-Pelayo C. Martínez-Quiñones J. Gil J. Durango D. Coumarins from the peel of citrus grown in Colombia: composition, elicitation and antifungal activity Heliyon 5 6 2019 110231
2 Satari B. Karimi K. Citrus processing wastes: environmental impacts, recent advances, and future perspectives in total valorization Res. Conserv. Recyc. 129 2018 153 167
3 Singh B. Singh J.P. Kaur A. Yadav M.P. Insights into the chemical composition and bioactivities of citrus peel essential oils Food Res. Int. 143 2021 110231
4 Guo J.-j. Gao Z.-p. Xia J.-l. Ritenour M.A. Li G.-y. Shan Y. Comparative analysis of chemical composition, antimicrobial and antioxidant activity of citrus essential oils from the main cultivated varieties in China LWT-Food Sci. Technol. 97 2018 825 839
5 Li J. Liu H. Mazhar M.S. Quddus S. Suleria H.A.R. LC-ESI-QTOF-MS/MS profiling of phenolic compounds in Australian native plums and their potential antioxidant activities Food Biosci. 52 2023 102331
6 Liaqat I. Riaz N. Saleem Q.-u.-A. Tahir H.M. Arshad M. Arshad N. Toxicological evaluation of essential oils from some plants of Rutaceae family Evid. Based Complement. Alternat. Med. 2018 2018
7 Rafiq S. Kaul R. Sofi S. Bashir N. Nazir F. Nayik G.A. Citrus peel as a source of functional ingredient: a review J. Saudi Soc. Agric. Sci. 17 4 2018 351 358
8 Guimarães R. Barros L. Barreira J.C. Sousa M.J. Carvalho A.M. Ferreira I.C. Targeting excessive free radicals with peels and juices of citrus fruits: grapefruit, lemon, lime and orange Food Chem. Toxicol. 48 1 2010 99 106 19770018
9 Lai C.-S. Li S. Miyauchi Y. Suzawa M. Ho C.-T. Pan M.-H. Potent anti-cancer effects of citrus peel flavonoids in human prostate xenograft tumors Food Funct. 4 6 2013 944 949 23673480
10 Lang A. 9 Benefits and Uses of Lemon Peel 2019 healthline
11 Yaghmaie P. Parivar K. Haftsavar M. Effects of Citrus Aurantifolia Peel Essential Oil on Serum Cholesterol Levels in Wistar Rats 2011
12 Matsuura R. Ukeda H. Sawamura M. Tyrosinase inhibitory activity of citrus essential oils J. Agric. Food Chem. 54 6 2006 2309 2313 16536612
13 Campolo O. Romeo F.V. Algeri G.M. Laudani F. Malacrinò A. Timpanaro N. Palmeri V. Larvicidal effects of four citrus peel essential oils against the arbovirus vector Aedes albopictus (Diptera: Culicidae) J. Econ. Entomol. 109 1 2016 360 365 26357845
14 Moosavy M. Hassanzadeh P. Mohammadzadeh E. Mahmoudi R. Khatibi S. Mardani K. Antioxidant and antimicrobial activities of essential oil of lemon (citrus limon) peel in vitro and in a food model J. Food Qual. Haz. Cont. 4 2 2017
15 Geraci A. Di Stefano V. Di Martino E. Schillaci D. Schicchi R. Essential oil components of orange peels and antimicrobial activity Nat. Prod. Res. 31 6 2017 653 659 27535797
16 Tao N.g. Liu Y.j. Zhang M.l. Chemical composition and antimicrobial activities of essential oil from the peel of bingtang sweet orange (Citrus sinensis Osbeck) Int. J. Food Sci. Technol. 44 7 2009 1281 1285
17 Mahmoud E.A. Essential oils of citrus fruit peels antioxidant, antibacterial and additive value as food preservative J. Food Dairy Sci. 8 2 2017 111 116
18 Raspo M.A. Vignola M.B. Andreatta A.E. Juliani H.R. Antioxidant and antimicrobial activities of citrus essential oils from Argentina and the United States Food Biosci. 36 2020 100651
19 Ishfaq M. Akhtar B. Muhammad F. Sharif A. Akhtar M.F. Hamid I. Sohail K. Muhammad H. Antioxidant and Wound healing potential of essential oil from Citrus reticulata peel and its chemical characterization Curr. Pharm. Biotechnol. 22 8 2021 1114 1121 32957881
20 Denkova-Kostova R. Teneva D. Tomova T. Goranov B. Denkova Z. Shopska V. Slavchev A. Hristova-Ivanova Y. Chemical composition, antioxidant and antimicrobial activity of essential oils from tangerine (Citrus reticulata L.), grapefruit (Citrus paradisi L.), lemon (Citrus lemon L.) and cinnamon (Cinnamomum zeylanicum Blume) Z. Naturforsch. C 76 5–6 2021 175 185 33909955
21 Dosoky N.S. Setzer W.N. Biological activities and safety of Citrus spp. essential oils Int. J. Mol. Sci. 19 7 2018 1966 29976894
22 Shehata S.A. Abdeldaym E.A. Ali M.R. Mohamed R.M. Bob R.I. Abdelgawad K.F. Effect of some citrus essential oils on post-harvest shelf life and physicochemical quality of strawberries during cold storage Agronomy 10 10 2020 1466
23 Njoroge S.M. Koaze H. Karanja P.N. Sawamura M. Volatile constituents of redblush grapefruit (Citrus paradisi) and pummelo (Citrus grandis) peel essential oils from Kenya J. Agric. Food Chem. 53 25 2005 9790 9794 16332132
24 Njoroge S.M. Koaze H. Mwaniki M. Minh Tu N. Sawamura M. Essential oils of Kenyan Citrus fruits: volatile components of two varieties of mandarins (Citrus reticulata) and a tangelo (C. paradisi× C. tangerina) Flav. Fragr. J. 20 1 2005 74 79
25 Bhattacharya S. Bhattacharya A. Sairam K. Ghosal S. Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study Phytomed 7 6 2000 463 469
26 Ortuño A. Báidez A. Gómez P. Arcas M. Porras I. García-Lidón A. Del Río J. Citrus paradisi and Citrus sinensis flavonoids: their influence in the defence mechanism against Penicillium digitatum Food Chem. 98 2 2006 351 358
27 Díaz‐Juárez J. Tenorio‐López F. Zarco‐Olvera G. Valle‐Mondragón L.d. Torres‐Narváez J. Pastelín‐Hernández G. Effect of Citrus paradisi extract and juice on arterial pressure both in vitro and in vivo Phytother Res. 23 7 2009 948 954 19153985
28 Heggers J.P. Cottingham J. Gusman J. Reagor L. McCoy L. Carino E. Cox R. Zhao J.-G. The effectiveness of processed grapefruit-seed extract as an antibacterial agent: II. Mechanism of action and in vitro toxicity J. Alternative Compl. Med. 8 3 2002 333 340
29 Giamperi L. Fraternale D. Bucchini A. Ricci D. Antioxidant activity of Citrus paradisi seeds glyceric extract Fitoterapia 75 2 2004 221 224 15030930
30 Özogul Y. Özogul F. Kulawik P. The antimicrobial effect of grapefruit peel essential oil and its nanoemulsion on fish spoilage bacteria and food-borne pathogens LWT-Food Sci. Technol. 136 2021 110362
31 Okunowo W.O. Oyedeji O. Afolabi L.O. Matanmi E. Essential Oil of Grape Fruit (Citrus Paradisi) Peels and its Antimicrobial Activities 2013
32 Oboh G. Ademosun A. Phenolic extracts from grapefruit peels (Citrus paradisi) inhibit key enzymes linked with type 2 diabetes and hypertension J. Food Biochem. 35 6 2011 1703 1709
33 Deng W. Liu K. Cao S. Sun J. Zhong B. Chun J. Chemical composition, antimicrobial, antioxidant, and antiproliferative properties of grapefruit essential oil prepared by molecular distillation Molecules 25 1 2020 217 31948058
34 Gillani R. Pakistan Citrus, Trade Development Authority of Pakistan 2019 Ministry of Commerce
35 Khan M.N. Characterization of essential oil of local varieties of Citrus paradisi Peel J. Chem. Soc. Pak. 32 6 2010 571
36 Roberto D. Micucci P. Sebastian T. Graciela F. Anesini C. Antioxidant activity of limonene on normal murine lymphocytes: relation to H2O2 modulation and cell proliferation Basic Clin. Pharmacol. Toxicol. 106 1 2010 38 44 19796276
37 Vieira A.J. Beserra F.P. Souza M. Totti B. Rozza A. Limonene: aroma of innovation in health and disease Chem. Biol. Inter. 283 2018 97 106
38 Saleem M. Shazmeen N. Nazir M. Riaz N. Zengin G. Ataullah H.M. Nisar F. Mukhtar M. Tousif M.I. Investigation on the phytochemical composition, antioxidant and enzyme inhibition potential of Polygonum Plebeium R. Br: a comprehensive approach to disclose new nutraceutical and functional food ingredients Chem. Biodivers. 18 12 2021 e2100706
39 Zubair M. Nazir M. Saleem M. Raiz N. Touseef S. Khan S. Zengin G. Ehsan Mazhar M. Imran Tousif M. Chemodiversity, biological activities and molecular docking studies of leptadenia pyrotechnica (forssk.) decne: a comprehensive approach to validate its medicinal use Chem. Biodivers. 19 5 2022 e202100884
40 Mollica A. Zengin G. Locatelli M. Stefanucci A. Mocan A. Macedonio G. Carradori S. Onaolapo O. Onaolapo A. Adegoke J. Anti-diabetic and anti-hyperlipidemic properties of Capparis spinosa L.: in vivo and in vitro evaluation of its nutraceutical potential J. Funct.Foods 35 2017 32 42
41 Zubair M. Nazir M. Saleem M. Raiz N. Touseef S. Khan S. Zengin G. Ehsan Mazhar M. Imran Tousif M. Chemodiversity, biological activities and molecular docking studies of leptadenia pyrotechnica (forssk.) decne: a comprehensive approach to validate its medicinal use Chem. Biodivers. 2022 e202100884
42 Paramashivam S.K. Elayaperumal K. bhagavan Natarajan B. devi Ramamoorthy M. Balasubramanian S. Dhiraviam K.N. In silico pharmacokinetic and molecular docking studies of small molecules derived from Indigofera aspalathoides Vahl targeting receptor tyrosine kinases Bioinformation 11 2 2015 73 25848167
43 Kim S. Chen J. Cheng T. Gindulyte A. He J. He S. Li Q. Shoemaker B.A. Thiessen P.A. Yu B.J.N.a.r. PubChem 2019 update: improved access to chemical data 47 D1 2019 D1102 D1109
44 Sussman J.L. Lin D. Jiang J. Manning N.O. Prilusky J. Ritter O. Abola E.E. Protein Data Bank (PDB): database of three-dimensional structural information of biological macromolecules Acta Crystallogr. Sect. D. Biol. Crystallogr. 54 6 1998 1078 1084 10089483
45 Morris G.M. Huey R. Lindstrom W. Sanner M.F. Belew R.K. Goodsell D.S. Olson A.J. AutoDock 4 and AutoDockTools 4: automated docking with selective receptor flexibility J. Comput. Chem. 30 16 2009 2785 2791 19399780
46 Saleem M. Nazir M. Riaz N. Tousif M.I. Tauseef S. Hassan L. Zengin G. Sharifi-Rad M. Shah S.A.A. Secondary metabolite profiling, antioxidant capacity, enzyme inhibitory potential and in silico studies of Launaea intybacea (Jacq.) Beauverd: a multifunctional approach to probe into the new nutraceuticals J. Mol. Struct. 2023 136480
47 Biovia D.S. Discovery Studio Visualizer, San Diego, CA, USA 2017 936
48 Adebisi O. Comparative study of essential oil composition of fresh and dry peel and seed of Citrus sinensis (L) Osbeck var shamuti and Citrus Paradise Macfadyen var Marsh IFE J. Sci. 16 2 2014 211 217
49 Nguyen Y.T.-K. To N.B. Truong V.N.-P. Kim H.Y. Ediriweera M.K. Lim Y. Cho S.K. Impairment of glucose metabolism and suppression of stemness in MCF-7/SC human breast cancer stem cells by nootkatone Pharmaceutics 14 5 2022 906 35631492
50 Miyazawa M. Hideyukitougo Ishihara M. Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi Nat. Prod. Lett. 15 3 2001 205 210 11858553
51 Gupta V. Kohli K. Ghaiye P. Bansal P. Lather A. Pharmacological potentials of Citrus paradisi-an overview Int. J. Phytother Res. 1 1 2011 8 17
52 Karioti A. Skaltsa H. Gbolade A.A. Constituents of the distilled essential oils of Citrus reticulata and C. paradisi from Nigeria J. Essent. Res. 19 6 2007 520 522
53 Javed S. Javaid A. Nawaz S. Saeed M. Mahmood Z. Siddiqui S. Ahmad R. Phytochemistry, GC-MS analysis, antioxidant and antimicrobial potential of essential oil from five citrus species J. Agric. Sci. 6 3 2014 201
54 Frassinetti S. Caltavuturo L. Cini M. Della Croce C. Maserti B. Antibacterial and antioxidant activity of essential oils from Citrus spp J. Essent. Oil Res. 23 1 2011 27 31
55 Vallinayagam S. Rajendran K. Sekar V. Green synthesis and characterization of silver nanoparticles using Naringi crenulate leaf extract: key challenges for anticancer activities J. Mol. Struct. 1243 2021 130829
56 Li C. Cai Q. Wu X. Tan Z. Huang S. Wei C. Zhang W. Chen Z. Zhang L. Xiang H. Variation in compositions and biological activities of essential oils from four citrus species: citrus limon, Citrus sinensis, Citrus paradisi, and Citrus reticulata Chem. Biodivers. 19 4 2022 e202100910
57 Ahmed S. Rattanpal H.S. Gul K. Dar R.A. Sharma A. Chemical composition, antioxidant activity and GC-MS analysis of juice and peel oil of grapefruit varieties cultivated in India J. Integr. Agric. 18 7 2019 1634 1642
58 Li Y. Liu S. Zhao C. Zhang Z. Nie D. Tang W. Li Y. The chemical composition and antibacterial and antioxidant activities of five citrus essential oils Molecules 27 20 2022 7044 36296637
59 Manzur M. Luciardi M.C. Blázquez M.A. Alberto M.R. Cartagena E. Arena M.E. Citrus sinensis essential oils an innovative antioxidant and antipathogenic dual strategy in food preservation against spoliage bacteria Antioxidants 12 2 2023 246 36829805
60 Gargouri B. Amor I.B. Messaoud E.B. Elaguel A. Bayoudh A. Kalle I. Hammadi A. Antioxidant capacity and antitumoral activity of Citrus paradisi essential oil, Biomedical J. Sci. Tech. Res. 40 2 2021 32121 32141
61 Himed L. Merniz S. Monteagudo-Olivan R. Barkat M. Coronas J. Antioxidant activity of the essential oil of citrus limon before and after its encapsulation in amorphous SiO2 Sci. Afr. 6 2019 e00181
62 Marzouk B. Characterization of bioactive compounds in Tunisian bitter orange (Citrus aurantium L.) peel and juice and determination of their antioxidant activities BioMed Res. Int. 2013 2013
63 Ou M.-C. Liu Y.-H. Sun Y.-W. Chan C.-F. The composition, antioxidant and antibacterial activities of cold-pressed and distilled essential oils of Citrus paradisi and Citrus grandis (L.) Osbeck Evid. Based Complement. Alternat. Med. 2015 2015
64 Aazza S. Lyoussi B. Megias C. Cortes-Giraldo I. Vioque J. Figueiredo A.C. Miguel M.G. Anti-oxidant, anti-inflammatory and anti-proliferative activities of Moroccan commercial essential oils Nat. Prod. Commun. 9 4 2014 1934578X1400900442
65 Job J.T. Visakh N.U. Pathrose B. Alfarhan A. Rajagopal R. Thayyullathil J. Thejass P. Ramesh V. Narayanankutty A. Chemical composition and biological activities of the essential oil from citrus reticulata Blanco peels collected from agrowastes Chem. Biodivers. 21 3 2024 e202301223
66 Narayanankutty A. Visakh N.U. Sasidharan A. Pathrose B. Olatunji O.J. Al-Ansari A. Alfarhan A. Ramesh V. Chemical composition, antioxidant, anti-bacterial, and anti-cancer activities of essential oils extracted from Citrus limetta Risso peel waste remains after commercial use Molecules 27 23 2022 8329 36500421
67 Aumeeruddy-Elalfi Z. Gurib-Fakim A. Mahomoodally M. Kinetic studies of tyrosinase inhibitory activity of 19 essential oils extracted from endemic and exotic medicinal plants S. Afr. J. Bot. 103 2016 89 94
68 Hu J. Li X. Liu X. Zhang W. Inhibitory effect of lemon essential oil on mushroom tyrosinase activity in vitro Mod. Food Sci. Technol 31 2015 97 105
69 Capetti F. Tacchini M. Marengo A. Cagliero C. Bicchi C. Rubiolo P. Sgorbini B. Citral-containing essential oils as potential tyrosinase inhibitors: a bio-guided fractionation approach Plants 10 5 2021 969 34068076
70 Yang J. Lee S.-Y. Jang S.-K. Kim K.-J. Park M.-J. Inhibition of melanogenesis by essential oils from the citrus cultivars peels Int. J. Mol. Sci. 24 4 2023 4207 36835634
71 da Silva A.P. Silva N.d.F. Andrade E.H.A. Gratieri T. Setzer W.N. Maia J.G.S. da Silva J.K.R. Tyrosinase inhibitory activity, molecular docking studies and antioxidant potential of chemotypes of Lippia origanoides (Verbenaceae) essential oils PLoS One 12 5 2017 e0175598
72 Shalaby A.S. Eid H.H. El‐Shiekh R.A. Youssef F.S. Al‐Karmalawy A.A. Farag N.A. Sleem A.A. Morsy F.A. Ibrahim K.M. Tadros S.H. A comparative GC/MS analysis of citrus essential oils: unveiling the potential benefits of herb‐drug interactions in preventing paracetamol‐induced hepatotoxicity Chem. Biodivers. 20 9 2023 e202300778
73 Dang N.H. Nhung P.H. Mai Anh B.T. Thu Thuy D.T. Minh C.V. Dat N.T. Chemical composition and α-glucosidase inhibitory activity of Vietnamese citrus peels essential oils J. Chem. 2016 2016
74 Oboh G. Olasehinde T.A. Ademosun A.O. Inhibition of enzymes linked to type-2 diabetes and hypertension by essential oils from peels of orange and lemon Int. J. Food Prop. 20 sup1 2017 S586 S594
75 Oboh G. Akinbola I.A. Ademosun A.O. Sanni D.M. Odubanjo O.V. Olasehinde T.A. Oyeleye S.I. Essential oil from clove bud (Eugenia aromatica Kuntze) inhibit key enzymes relevant to the management of type-2 diabetes and some pro-oxidant induced lipid peroxidation in rats pancreas in vitro J. Oleo Sci. 64 7 2015 775 782 25994557
76 Hamden K. Keskes H. Belhaj S. Mnafgui K. Feki A. Allouche N. Inhibitory potential of omega-3 fatty and fenugreek essential oil on key enzymes of carbohydrate-digestion and hypertension in diabetes rats Lipids Health Dis. 10 2011 1 10
77 Sahin Basak S. Candan F. Chemical composition and in vitro antioxidant and antidiabetic activities of Eucalyptus camaldulensis Dehnh essential oil, J. Iranian Chem. Soc. 7 2010 216 226
78 Guo Y. Hou E. Ma N. Liu Z. Fan J. Yang R. Discovery, biological evaluation and docking studies of novel N-acyl-2-aminothiazoles fused (+)-nootkatone from Citrus paradisi Macf. as potential α-glucosidase inhibitors Bioorg. Chem. 104 2020 104294
