Herbal Arsenal against Skin Ailments: A Review Supported by In Silico Molecular Docking Studies

Abstract

Maintaining healthy skin is important for a healthy body. At present, skin diseases are numerous, representing a major health problem affecting all ages from neonates to the elderly worldwide. Many people may develop diseases that affect the skin, including cancer, herpes, and cellulitis. Long-term conventional treatment creates complicated disorders in vital organs of the body. It also imposes socioeconomic burdens on patients. Natural treatment is cheap and claimed to be safe. The use of plants is as old as mankind. Many medicinal plants and their parts are frequently used to treat these diseases, and they are also suitable raw materials for the production of new synthetic agents. A review of some plant families, viz., Fabaceae, Asteraceae, Lamiaceae, etc., used in the treatment of skin diseases is provided with their most common compounds and in silico studies that summarize the recent data that have been collected in this area.

1. Introduction

Molecular docking is an in silico procedure that is able to predict the mechanism of binding of a suggested ligand to its macromolecular target during the formation of a stable complex. Therefore, docking has become of great importance for the illustration of molecular interactions of natural compounds with different receptors [1,2,3].

The skin, the largest organ of the human body, functions as a physical barrier and an exterior interface of the body with the outer environment. The skin prevents the body from the invasion of external pathogens, as well as mechanical, thermal, and physical injuries from any substance that can be hazardous to humans. Just like any other organ and system of the body, this system is also very complex. The skin, with its derivatives such as nails, sweat glands, oil glands, and hair, makes up the integumentary system [4]. It is an incredible organ that protects the whole body. It consists of three main layers, including the epidermis (outermost layer), which consists of three types of cells, i.e., squamous cells, basal cells, and melanocytes; the second layer of the skin, the dermis, which contains blood and lymph vessels, hair follicles, etc.; and the subcutaneous fat layer. The focus on skin health is because everyone wants clearer, healthier, younger, and fresher skin, as skin-related complications can cause problems related to mental health, as well as low self-esteem [5].

Herbal medicine can be traced back to ancient civilizations. It entails the use of plants for medicinal purposes to cure illnesses and improve overall health [6]. Although herbal plants are low in toxicity and readily available, they play an important role in not only pharmacological research and drug production but also as plant components, being used specifically as therapeutic agents for drug synthesis [7]. The most widely used plant parts in the preparation of traditional medicines are the leaves (62%), either alone or in combination with other plant parts [6,7].

Skin disease refers to problems with the surface layer of the skin. Skin disorders have a serious impact on well-being and are difficult to manage due to their persistence [8]. Several microorganisms trigger skin ailments, including boils, scratching ringworm, skin diseases, leprosy, injury, skin infections, eczema, skin allergy inflammation, scabies, and psoriasis [9].

Scabies, a parasitic infection, has always been the most prevalent skin disorder, but, in some areas, it is entirely absent [10]. Sarcoptes scabiei is the mite that causes scabies. Infection with the scabies worm causes a rash of vesicles, nodules, and papules. The majority of this is due to host hypersensitivity, but the direct impact of worm invasion also plays a significant role [11].

A rash is a red, inflamed patch of skin or a set of discrete spots. Irritation, inflammation and allergies, fundamental conditions, and structural issues may all contribute to these symptoms. Acne, eczema, psoriasis, hives, etc., are causes of rashes [4].

Atopic eczema, a chronic condition that affects people who are genetically organized to overreact towards environmental stimuli, has become an inflammatory disease. It is often seen in people with asthma, allergic rhinitis, and atopy symptoms. Eczema is a common skin problem in children. Severe skin dryness and inflammation, scaly patches, redness, and lichenified plaque with abrasions are the most common dermatitis symptoms [12].

Acne is a contagious disease and one of the most common in humans. Acne leads to seborrhea, papules, comedowns, blackheads, nodules, and scars [13]. Acne is most often found on the face, chest area, and back of people who have a large number of oil glands [14].

Psoriasis is an inflammatory skin problem that causes keratinocytes, excessive proliferation resulting in scaly patches, extreme inflammation, and erythema [15].

The uncontrolled development of cells present in the skin is known as skin cancer. It occurs due to unfixed DNA damage to skin cells, most commonly due to UV from sunlight, causing mutations and even genetic abnormalities. This causes skin cells to grow rapidly, resulting in the formation of malignant tumors [16].

A burn is considered tissue damage due to fire, chemicals, or radiation. Burn wounds are classified as superficial, partial thickness, or full thickness. Swelling, epithelization, wound contraction, and granulation are all part of the healing process after a burn wound [17].

The current review presents the effect of different medicinal plants and FDA-approved formulas on the management of various skin disorders. A molecular docking study was conducted for major components of these medicinal plants on the active sites of granzyme B and human leukocyte elastase (HLE) enzymes, aiming to identify the potential compounds or class of compounds that may be responsible for the ameliorative effects on different skin ailments.

2. Medicinal Plants and Skin Disorders

Medicinal plants reported for the management of skin disorders (Table 1) are classified below according to their uses.

Table 1.

Botanical sources and medicinal plants used to treat different skin disorders.

No.	Botanical Source (Latin Name, Common Name, Family)	Uses	References
A	Medicinal Plants Used to Treat Skin infections
1	Achyranthes aspera	Used to treat boils and scabies	[18]
	Prickly chaff flower
	Family Amaranthaceae
2	Aconitum chasmanthum	Used to treat mumps and measles	[19]
	Gaping monkshood
	Family Ranunculaceae
3	Butea monosperma	Used to treat skin diseases such as inflammation	[20]
	Flame of forest
	Family Fabaceae
4	Boerhavia diffusa	Used to treat abscesses	[21]
	Tar vine, wine flower
	Family Nyctaginaceae
5	Curcuma longa	Used to treat skin inflammation	[22]
	Turmeric
	Family Zingiberaceae
6	Crocus sativus	Used to treat psoriasis	[23]
	saffron
	Family Iridaceae
7	Commelina benghalensis	Used to treat wound infection	[24]
	Tropical spiderwort
	Family Commelinaceae
8	Cyperus difformis	Used to treat skin infections	[25]
	Family Cyperaceae
9	Cassia tora	Used to treat psoriasis	[26]
	Stinking cassia
	Family Caesalpiniaceae
10	Capsicum frutescens	Used to treat psoriasis	[27]
	Chilli
	Family Solanaceae
11	Dalbergia sissoo	Used to treat abscesses	[28]
	North Indian rosewood
	Family Fabaceae
12	Eucalyptus globulus	Used to treat acne, fungal infections, and heal wounds	[29]
	Eucalyptus
	Family Myrtaceae
13	Euphorbia wallichii	Used to treat skin infections and warts	[30]
	Wallich spurge
	Family Euphorbiaceae
14	Ficus carica	Used to treat itching, pimples, and scabies	[31]
	Fig
	Family Moraceae
15	Fagopyrum tataricum	Used to treat erysipelas	[32]
	Tartary buckwheat
	Family Polygonaceae
16	Gnaphalium affine	Used to treat weeping pruritus of skin	[33]
	Cotton weed
	Family Asteraceae
17	Juniperus excelsa	Used to treat skin infections	[34]
	Eastern savin
	Family Cupressaceae
18	Lens culinaris	Used to treat skin infections and acne	[35]
	Lentil
	Family Fabaceae
19	Marsilea quadrifolia	Used to treat abscesses	[36]
	Water clover
	Family Marsileaceae
20	Mahonia aquifolium	Used to treat psoriasis	[37]
	Oregon grape
	Family Berberidaceae
21	Pleurospermum brunonis	Used to treat skin infections	[38]
	Brown’s paper cup flower
	Family Apiaceae
22	Pinus roxburghii	Used to treat pruritus, inflammation, and other skin diseases	[39]
	Chir pine
	Family Pinaceae
23	Pinus wallichiana	Used to treat wound infection	[40]
	Bhutan pine
	Family Pinaceae
24	Rubia cordifolia	Used to treat psoriasis	[41]
	Common madder
	Family Rubiaceae
25	Solanum nigrum	Used to treat pimples, pustules, ringworms, eczema, syphilitic ulcers, and leukoderma	[42,43]
	Black nightshade
	Family Solanaceae
26	Simmondsia chinensis	Used to treat acne and psoriasis	[44]
	Jojoba
	Family Buxaceae
27	Taxus wallichiana	Used to treat psoriasis and ringworm	[45]
	Himalayan yew
	Family Taxaceae
28	Tectona grandis	Used to treat pruritus and heal wounds	[46,47]
	Teak
	Family Lamiaceae
29	Thespesia populne	Used to treat psoriasis	[48]
	Indian tulip tree
	Family Malvaceae
30	Wrightia tinctoria	Used to treat psoriasis	[49]
	Sweet indrajao
	Family Apocynaceae
B	Medicinal Plants Used to Treat Eczema
31	Abrus precatorious	Used to treat eczema	[50]
	Rosary pea
	Family Fabaceae
32	Avena sativa	Used to treat eczema, wounds, inflammation, itching, burns, and irritation	[51]
	Oat
	Family Poaceae
33	Arnebia euchroma	Used to treat burns, eczema, and dermatitis	[52,53]
	Pink arnebia
	Family Boraginaceae
34	Actinidia deliciosa	Used to treat inflammation and eczema	[54]
	Kiwi fruit
	Family Actinidiaceae
35	Aristolochia indica	Used to treat eczema and wounds	[55]
	Indian birthwort
	Family Aristolochiaceae
36	Betula alba	Used to treat eczema, psoriasis, and acne	[56]
	Paper birch
	Family Betulaceae
37	Cannabis sativus	Used to treat sores, eczema, dermatitis, psoriasis, seborrheic, and lichen planus	[57]
	Charas, ganja
	Family Cannabaceae
38	Matricaria chamomilla	Used to treat eczema and skin inflammation	[58,59]
	Chamomile
	Family Asteraceae
39	Sarco asoca	Used to treat skin diseases, inflammation, eczema, and scabies	[60]
	Ashoka
	Family Caesalpiniaceae
40	Saponaria officinalis	Used to treat eczema, acne, boils, and psoriasis	[61,62]
	soapworts
	Family Caryophyllaceae
41	Vitex negundo	Used to treat skin diseases such as eczema, acne, pimples, ringworms, etc.	[35]
	Nirgundi
	Family Verbenaceae
C	Medicinal Plants Used for Wound healing
42	Achillea millefolium	Used to treat burn wounds	[63]
	Common Yarrow
	Family Asteraceae
43	Albizia lebbeck	Used for wound healing, leucoderma, itching, and inflammation	[64]
	Siris
	Family Fabaceae
44	Allium sativum	Used to treat psoriasis, scars, and heal wounds	[65]
	Garlic
	Family Alliaceae
45	Aloe barbadensis	Used to treat skin injuries	[66]
	Aloe vera
	Family Aloeaceae
46	Alternanthera brasiliana	Used to heal inflammation wounds	[64]
	Brazilian joyweed
	Family Amaranthaceae
47	Abelmoschus esculentus	Used to cure pimples and wounds	[67]
	Okra
	Family Malvaceae
48	Adiantum venustum D	Used to heal wounds	[68]
	Himalayan maidenhair
	Family Pteridaceae
49	Argemone Mexicana	Used to treat wounds	[69]
	Mexican poppy
	Family Papaveraceae
50	Alkanna tinctoria	Used to treat itching, skin wounds, and rashes	[70]
	Alkanet
	Family Boraginaceae
51	Brassica oleracea	Used to treat dermatitis and wounds	[71]
	Red cabbage
	Family Brassicaceae
52	Berberis lycium	Used to heal wounds	[72]
	Indian lycium
	Family Berberidaceae
53	Bergenia ciliata	Used to heal wounds	[73,74]
	Winter begonia
	Family Saxifragaceae
54	Bergenia ligulata	Used to heal wounds and treat boils	[75]
	Asmabhedaka
	Family Saxifragaceae
55	Bauhinia purpurea	Used to heal wounds and treat inflammation	[76]
	Orchid tree
	Family Fabaceae
56	Carissa spinarum	Used to heal wounds and treat boils	[77]
	Bush plum
	Family Apocynaceae
57	Cannabis sativa	Used to treat dandruff and heal wounds	[78]
	Marijuana, hemp
	Family Cannabaceae
58	Capparis decidua	Used to heal wounds	[79]
	Bare caper
	Family Capparaceae
59	Cynodon dactylon	Used to heal wounds and skin problems	[80,81]
	Bermuda grass
	Family Poaceae
60	Cocos nucifera	Used to treat skin wounds	[82]
	Coconut
	Family Arecaceae
61	Euphorbia helioscopia	Used to heal wounds	[83,84]
	Sun spurge
	Family Euphorbiaceae
62	Ferula foetida	Used to heal wounds	[85]
	Asafoetida, Hing
	Family Apiaceae
63	Ficus benghalensis	Used to treat skin injuries	[86]
	Banyan tree
	Family Moraceae
64	Gerbera gossypina	Used to heal wounds	[87]
	Hairy gerbera daisy
	Family Asteraceae
65	Galium aparine	Used to treat wounds as an antiseptic	[88]
	Goosegrass
	Family Rubiaceae
66	Hackelia americana	Used to treat wounds, tumors, and inflammation	[89]
	Nodding stickseed
	Family Boraginaceae
67	Hypericum perforatum	Used to treat wounds, abrasions, inflammatory skin disease, and burns	[90]
	Perforatejohn’s wort
	Family Hypericaceae
68	Isodon rugosus	Used to heal wounds	[91]
	Wrinkled leaf isodon
	Family Lamiaceae
69	Launaea nudicaulis	Used to heal wounds	[92]
	Bhatal
	Family Asteraceae
70	Momordica charantia	Used to heal wounds	[93]
	Bitter gourd
	Family Cucurbitaceae
71	Micromeria biflora	Used to heal wounds and treat skin infections	[94]
	Lemon savory
	Family Lamiaceae
72	Nigella sativa	Used to heal wounds	[95,96]
	Black cumin
	Family Ranunculaceae
73	Plantago major	Used to treat wounds	[97]
	Great plantain
	Family Plantaginaceae
74	Plantago lanceolata	Used to heal wounds	[98]
	Ribwort plantain
	Family Plantaginaceae
75	Rumex dissectus	Used to stop wound bleeding	[99]
	Arrowleaf dock
	Family Polygonaceae
76	Salvia moorcroftiana	Used to treat skin itching and wound healing	[100]
	Kashmir salvia
	Family Lamiaceae
77	Trigonella foenum-graecum	Used to heal wounds	[101,102]
	Fenugreek
	Family Fabaceae
78	Tephrosia purpurea	Used to heal wounds	[103]
	Wild indigo
	Family Fabaceae
79	Urtica dioica	Used to heal wounds	[104,105]
	Stinging nettle
	Family Urticaceae
80	Verbascum Thapsus	Used to treat pimples, heal wounds, and treat other skin problems	[106]
	Common mullein
	Family Scrophulariaceae
D	Medicinal Plants Used to Treat Skin Burns
81	Astilbe thunbergii	Used to treat burns	[107]
	Astilbe
	Family Saxifragaceae
82	Anaphalis margaritacea	Used to treat sunburn	[108]
	Pearly everlasting
	Family Asteraceae
83	Aquilegia pubiflora	Used to heal wounds and treat skin burns	[109]
	Himalayan columbine
	Family Ranunculaceae
84	Amygdalus communis	Used to treat burn wounds	[53]
	Almonds
	Family Rosaceae
85	Bergenia stracheyi	Used to treat sunstroke and heal wounds	[110]
	Himalayan Bergenia
	Family Saxifragaceae
86	Calendula officinalis	Used to treat burns and bruises	[111]
	Marigold
	Family Asteraceae
87	Cucumis melo	Used to treat skin burns	[112]
	Muskmelon
	Family Cucurbitaceae
88	Corydalis govaniana	Used to treat skin burns	[113]
	Govan’s corydalis
	Family Papaveraceae
89	Carica candamarcensis	Used to treat burn wounds	[114]
	Mountain papaya
	Family Caricaceae
90	Clitoria ternatea	Used to treat boils, acne, and skin outbreaks	[115]
	Butterfly pea
	Family Fabaceae
91	Datura stramonium	Used to treat boils	[116]
	Jimsonweed, thornapple
	Family Solanaceae
92	Dodonaea viscosa	Used to treat skin burns and heal wounds, acne, pimples, rashes, itching, and pustules	[117,118,119]
	Hop bush
	Family Sapindaceae
93	Echinacea angustifolia	Used to treat psoriasis, burns, acne, ulcers, and skin wounds	[120]
	Purple coneflower
	Family Asteraceae
94	Ginkgo biloba	Used to treat skin burns	[121]
	Maidenhair tree
	Family Ginkgoaceae
95	Hippophae rhamnoides	Used to treat rashes and skin burns	[122,123]
	Sea buckthorn
	Family Elaeagnaceae
96	Impatiens edgeworthii	Used to treat skin burns	[124]
	Edgeworth Balsam
	Family Balsaminaceae
97	Mangifera indica	Protect skin from sun damage	[125]
	Mango
	Family Anacardiaceae
98	Malus pumila	Used to treat boils	[126]
	Apple
	Family Rosaceae
99	Malva sylvestris	Used to treat burn wounds	[53]
	High mallow
	Family Malvaceae
100	Matricaria chamomilla	Used to treat burn wounds	[127]
	Chamomile
	Family Asteraceae
101	Onosma hispida	Used to treat skin burns	[128]
	Bristly onosma
	Family Boraginaceae
102	Portulaca oleracea	Used to treat burns, skin eruptions, rashes, skin inflammation, eczema, abscesses, and pruritus	[129,130,131]
	Purslane, little hogweed
	Family Portulacaceae
103	Pisum sativum	Used to treat skin burns	[132]
	Garden pea
	Family Fabaceae
104	Picrorhiza kurroa	Used to treat burning sensation	[133]
	Kutki
	Family Plantaginaceae
105	Rumex dentatus	Used to treat boils	[134]
	Toothed dock
	Family Polygonaceae
106	Rubus abchaziensis	Used to treat boils and wounds	[135]
	Akhray
	Family Rosaceae
107	Solanum virginianum	Used to treat swelling of skin	[136]
	Thorny nightshade
	Family Solanaceae
108	Scrophularia deserti	Used to treat burn wounds	[53]
	Desert figwort
	Family Scrophulariaceae
109	Sesamum indicum	Used to treat burn wounds	[137]
	Sesame
	Family Pedaliaceae
110	Silybum marianum	Used to treat burn wounds and improve skin health	[138]
	Blessed thistle
	Family Asteraceae
111	Tamarix aphylla	Used to treat skin burns and wounds	[139]
	Athel
	Family Tamaricaceae
112	Tridax procumbens	Used to treat burn wounds	[140]
	Coatbuttons, tridax daisy
	Family Asteraceae
113	Zanthoxylum armatum	Used to treat skin burns	[141]
	Winged prickly ash
	Family Rutaceae
E	Medicinal Plants Used to Treat Miscellaneous Disorders
114	Allium cepa	Used to treat skin lesions	[142]
	Garden onion
	Family Alliaceae
115	Azadirachta indica	Used to treat acne and protect skin from UV rays	[143]
	Neem
	Family Meliaceae
116	Anethum graveolens	Used to treat pimples	[144]
	Dill
	Family Apiaceae
117	Androsace rotundifolia lehm.	Used to treat skin problems	[145]
	Rock jasmine
	Family Primulaceae
118	Arnica montana	Used as anti-inflammatory to treat boils and acne eruptions	[146,147]
	Mountain arnica
	Family Asteraceae
119	Bauhinia variegata	Used to treat skin disease and skin ulcers	[148]
	Kachnar, orchid tree
	Family Fabaceae
120	Beta vulgaris	Used to treat tumors	[149]
	Beetroot
	Family Brassicaceae
121	Brassica juncea	Used against skin eruptions and ulcers	[150,151]
	Mustard
	Family Brassicaceae
122	Berberis aquifolium	Used to treat acne scars	[152]
	Oregon grape
	Family Berberidaceae
123	Camellia sinensis	Used to treat skin tumors and cancer	[153]
	Green Tea
	Family Theaceae
124	Coriandrum sativum	Used to treat pimples	[154,155]
	Dhaniya
	Family Apiaceae
125	Calotropis procera	Used to treat inflammation	[156]
	Giant milkweed
	Family Apocynaceae
126	Cerastium fontanum	Used to treat skin diseases; also acts as anti-inflammatory	[157]
	Mouse ear chickweed
	Family Caryophyllaceae
127	Citrus medica	Used to treat skin irritation	[158,159]
	Citron
	Family Rutaceae
128	Citrus sinensis	Used to treat pimples	[160]
	orange
	Family Rutaceae
129	Catharanthus roseus	Used to cure pimples	[161]
	Periwinkle
	Family Apocynaceae
130	Carthamus tinctorius	Used to treat eruptive skin problems	[162]
	safflower
	Family Asteraceae
131	Clerodendrum viscosum	Used as antiseptic skin wash	[163]
	Hill glory bower
	Family Verbenaceae
132	Equisetum arvense	Used to treat skin allergy	[164]
	Field horsetail
	Family Equisetaceae
133	Lavendula officinalis	Used to prevent and heal acne	[165]
	Lavender
	Family Labiatae
134	Lawsonia inermis	Used to treat inflammation and tumors	[166]
	Henna
	Family Lythraceae
135	Lycopersicon esculentum	Used to treat acne and sunburn	[167]
	Tomato
	Family Solanaceae
136	Ledum groenlandicum oedar	Used to treat itching, acne, and redness	[61]
	Labrador tea
	Family Ericaceae
137	Mirabilis jalapa	Used to treat allergic skin disorders	[168]
	Four o’clock
	Family Nyctaginaceae
138	Melia azedarach	Used to treat pimples and inflammation	[169]
	Persian lilac
	Family Meliaceae
139	Myrsine Africana	Used to treat skin disorders	[170]
	Cape myrtle
	Family Myrsinaceae
140	Melaleuca alternifolia	Used to treat acne	[171]
	Tea tree
	Family Myrtaceae
141	Olea europaea	Used as skin cleanser	[172]
	Olive tree
	Family Oleaceae
142	Ocimum sanctum	Used to treat acne and inflammation	[173,174]
	Tulsi
	Family Lamiaceae
143	Plumbago zeylanica	Used to treat skin diseases such as sores, acne, and dermatitis	[31]
	Doctor bush
	Family Plumbaginaceae
144	Prunus persica	Used to treat skin disorders	[175]
	Peach
	Family Rosaceae
145	Piper nigrum	Used to treat acne	[176]
	Black pepper
	Family Piperaceae
146	Pterocarpus santalinus	Used to treat skin inflammation and acne	[177]
	Red sandalwood
	Family Fabaceae
147	Rosmarinus officinalis	Used to block skin tumor cells	[178]
	Rosemary
	Family Lamiaceae
148	Ricinus communis	Used in children for skin diseases	[179]
	Castor oil plant
	Family Euphorbiaceae
149	Rheum officinale	Used to treat acne	[180]
	Rhubarb
	Family Polygonaceae
150	Salix babylonica	Used as skin cleanser	[181]
	Weeping willow
	Family Salicaceae
151	Serenoa repens	Used to treat acne and inflammation	[182]
	Saw palmetto
	Family Arecaceae
152	Thymus vulgaris	Used to treat cellulitis	[153]
	Thyme
	Family a
153	Taraxacum officinale	Used to treat pimples	[183]
	Common dandelion
	Family Asteraceae
154	Tussilago farfara	Used to treat sores and inflammation of skin	[184]
	coltsfoot
	Family Asteraceae
155	Valeriana jatamansi	Used to treat pimples	[185]
	Jatamansi
	Family Caprifoliaceae

3. Some Reported Mechanism of Action

The use of herbal medicine is becoming popular worldwide. Herbal medicines are preferred over synthetic medicines, as they produce fewer side effects [186,187,188,189]. Additionally, phytochemicals can treat skin ailments by different mechanisms and by displaying various biological activities such as antioxidant, anti-inflammatory, and antiallergic [190,191,192]. Each plant has its own bioactivity, which depends upon the chemical nature and potency of the constituents present in it [193,194]. Some components reduce skin inflammation by inhibiting NF-κB, for example, Zingiber officinale. The squeezed extract of this in rats and mice elevates TNF-α in peritoneal cells, and its long-term use can increase the level of serum corticosterone and thus reduce proinflammatory markers [195]. Drugs such as Rosmarisum officinalis also help in the improvement of abnormal skin conditions. It constitutes rosmarinic acid, which can disturb the system activation inhibition of the C3b attachment. It also acts on the inhibition and reduction of proinflammatory mediators such as TNF-α and IL-1 [196]. Oenothera biennis constitutes β-sitosterol, which modulates NO, TNF-α, IL-$1\beta$, and TXB2, leading to the suppression of COX-2 gene expression, hence causing anti-inflammatory action [197].

4. FDA-Approved Formulas

The Food and Drug Administration (FDA), as well as in vitro and in vivo study results, has approved bacterial cellulose (BC) and plant cellulose (PC) products to be incorporated into the biomedical field and their applications due to their biocompatibility with human cells and potential activity in wound healing and in the therapeutics field [198].

Moreover, honey, a natural product, is rich in several phenolic compounds, sugars, and enzymes that possess antioxidant, anticarcinogenic, anti-inflammatory, and antimicrobial activity. The main role of honey in the development of the wound healing process appeared to be via the acceleration of dermal repair and epithelialization, angiogenesis promotion, immune response promotion, and the reduction in healing-related infections with pathogenic microorganisms. The FDA approved many formulas containing honey as the main ingredient, among which is L-Mesitran^® (manufactured by Triticum Company—UK) Ointment, which consists of 48% medical-grade honey, lanolin, cod liver oil, sunflower oil, calendula, aloe vera, zinc oxide, and vitamins C and E. Additionally, Revamil Gel^® (manufactured by Maximed Pharrma—Lebanon) was FDA approved, containing 100% medical-grade honey, together with Therahoney^® Gel (manufactured by Medline Industries Inc.—USA), containing 100% Manuka honey [199].

5. Phytoconstituents of Medicinal Plants

Many phytochemical constituents have shown potential bioactivities, to which the biological activities of medicinal plant extracts can be attributed. Table 2 summarizes some of them in the context of treating skin disorders.

Table 2.

Selected reported phytoconstituents of herbal plants used to treat skin diseases.

Serial No.	Botanical Name	Some Phytoconstituents and/or Classes ofCompounds	Selected Structures	Ref.
1.	Abrus precatorious	Stigmasterol, β-sitosterol, and abrusogenin	Abrusogenin	[200]
2.	Achillea millefolium	Chlorogenic acid, apigenin-7-glucoside, and luteolin-7-glucoside	Chlorogenic acid	[201]
3.	Achyranthes aspera	Rutin, chlorogenic acid, and genistein	Genistein	[202]
4.	Allium cepa	Quercetin, S-methyl-L-cysteine, cycloalliin, N-acetylcysteine, S-propyl-L-cysteine sulfoxide, and dimethyl trisulfide	Cycloalliin N-acetyl cysteine S-methyl-L-cysteine	[203]
5.	Azadirachta indica	Nimbin, nimbanene, ascorbic acid, n-hexacosanol, nimbolide, 17-hydroxy azadiradione, 6-desacetyl nimbinene, and nimbandiol	Nimbin	[204]
6.	Albizia lebbeck	Lupeol, lupenone, luteolin, rutin, sapiol, friedelin, stigmasterol, β-sitosterol, stigmasterol-3-glucoside, β-sitosterol-3-glucoside, alkaloids as 3,3-dimethyl-4-(1-aminoethyl)-azetidin-2-one, 2-amino-4-hydroxy pteridine-6-carboxylic acid, and 2,4 bis(hydroxylamino)-5-nitropyrimidine	Lupeol	[205]
7.	Allium sativum	Alliin, allicin, S-allyl cysteine, diallyl sulfide, diallyl trisulfide, diallyl disulfide, and ajoene	Alliin	[206]
8.	Aloe barbadensis	Aloesin, cinnamic acid, isoaloresin D, caffeic acid, chlorogenic acid, aloin A and B, emodin, isovitexin, and orientin	Aloin	[207]
9.	Alternanthea brasiliana	Amaranthine, iso amaranthine, betanin, isobetanin, hydroxybenzoic acid, hydroxycinnamic acid, kaempferol glucoside, rhamnoside, and dirhamnosyl-glucoside	Amaranthine	[208]
10.	Anethumgraveolens	Limonene, carvone, α-phellandrene, β-phellandrene, and p-cymene	Limonene	[209]
11.	Avena sativa	Proteins, lipids, polysaccharides, β-glycan, dietary fibers, avenanthramides, gramine alkaloid, flavonolignans, flavonoids, saponins, and sterols	Avenanthramide A	[210]
12.	Arnebia euchroma	Shikonin, methyllasiodiplodin, euchroquinols A-C, and 9,17-epoxy arnebinol	Shikonin,	[211]
13.	Astilbe thunbergii	Eucryphin, astilbin, and berginin	Eucryphin	[107]
14.	Actinidia deliciosa	Rutin, quercitrin, quercetin, chrysin, and syringic acid	Quercetin	[212]
15.	Anaphalis margaritacea	Volatile oil contains E-caryophyllene, and its oxide, δ-cadinene, γ-cadinene, cubenol, ledol, and α-pinene	E-caryophyllene	[213]
16.	Abelmoschus esculentus	Quercetin-3-glucoside, diglucoside, catechins, and hydroxyl cinnamic acid derivatives	Quercetin-3-glucoside	[214]
17.	Adiantum venustum Don	Norlupane, noroleanane, lupane triterpenoids, adiantone, and 21-hydroxyadiantone (Norhopane)triterpenes	Adiantone	[215]
18.	Saponaria officinalis	Saponins	Cyclamin	[62]
19.	Aquilegia pubiflora	Orientin, coumaric acid, sinapic acid, chlorogenic acid, ferulic acid, vitexin, isoorientin, and isovitexin	Orientin	[216]
20.	Argemone mexicana	Berberine, oxyberberine, arginine, higenamine, pancorine, sanguinarine, β-amyrin, trans-phytol, luteolin, quercetin, quercitrin, and rutin	Berberine	[69]
21.	Arnica montana	Sesquiterpene lactones, phenolic acids, flavonoids, helenalin, acetyl helenalin, metacryl helenalin, chlorogenic acid, 3,5-dicaffeoylquinic acid, 4,5- dicaffeoylquinic acid, quercetin-3-glucoside, quercetin-3-glucuronide, kaempferol-3-glucoside, and kaempferol-3-glucuronide	Solaniol	[217]
22.	Alkanna tinctoria	Alkaloid, bufadienolides, carbohydrate, flavonoids, saponins, and tannins	Bufadienolide	[218]

6. Computational Studies

6.1. Methodology of Molecular Docking Studies

Based on the aforementioned, human granzyme B in complex with 2-acetamido-2-deoxy-beta-D-glucopyranose [219] was downloaded from PDB (Code: 1IAU), while the crystal structure of highly glycosylated human leukocyte elastase in complex with a thiazolidinedione inhibitor (5-[[4-[[(2~{S})-4-methyl-1-oxidanylidene-1-[(2-propylphenyl)amino]pentan-2-yl]carbamoyl]phenyl]methyl]-2-oxidanylidene-1,3-thiazol-1-ium-4-olate) [220] was also downloaded from PDB (Code: 6F5M). Both enzymes were cleaned for missing amino acids or gaps in their sequences. Hydrogens were added, water molecules were removed if present, and simulation for forcefield CHARMm and partial charge MMFF was applied. A heavy atom was built, and fixation of atom constraints was applied before enzyme minimization. The receptor was identified, and the binding site was highlighted from the complexed ligand, which was later cut off for the comparative docking study. The structures of the selected active constituents were downloaded from PubChem with the .svd extension and opened in the program. A simulation for all selected 23 active constituents was applied with the CHARMm forcefield and partial charge MMFF, and ligand preparation was carried out. The 23 resulting compounds, together with the reference ligand, were allowed to dock against both enzymes using the C-docker protocol.

6.2. Results and Discussion of Computational Studies

Molecular docking is of great importance for illustrating the molecular interactions of natural compounds with different receptors [221]. Although each docking program operates slightly differently, they share common features that involve ligand and receptor, sampling, and scoring. Thus, a molecular docking study was performed using the selected software Discovery Studio 4.1 [222,223,224]. Twenty-three interesting phytoconstituents of the previously detailed plants were selected for in silico docking trials to explore their activity and possible mechanism of binding against two essential enzymes human granzyme B and human leukocyte elastase, where the inhibition of either or both of those enzymes could aid in the treatment of various skin diseases.

The 2D interaction energy of the 23 active constituents compared to the reference ligand 2-acetamido-2-deoxy-beta-D-glucopyranose, together with their C-docker interaction energy, is displayed in Table 3. The ligand displayed –27.55 Kcal/mol, saponin showed –28.10 Kcal/mol, and the rest of the constituents showed –21.42 to –1.05 Kcal/mol. Both S-methyl-L-cysteine and N-acetyl cysteine were unsuccessful in the inhibition of granzyme B. The reference ligand performed its inhibitory action via four H-bonds with essential amino acids in the granzyme B sequence (Ala 93, Asn 98, Tyr 175, and Asp 176) and via van der Waals forces with six other amino acids (Asn 95, Ser 100, Asn 101, Ser 177, Thr 178, and Ile 179). Saponin was the only constituent better than the inhibitor, displaying better interaction energy and binding mode comparable to the ligand, as shown in Figure 1. Cyclamin saponin bounded by two H-bonds with Ser 100 and three H-bonds with Asn 101, Asp 176, and Thr178, while it displayed van der Waals force attractions with Asn 93, Asn 95, Asn 98, and Ile 179.

Table 3.

Results of molecular modeling study of 24 active constituents against human granzyme B (1IAU) compared to reference complexed ligand.

Serial No.	Compound	(C-Docker Interaction Energy)	2D Interaction Diagram *	Type of Binding
1	Ligand (reference)	−27.55		H-bond: Ala 93, Asn 98, Asp 176, Tyr 175 Van der Waals: Asn 95, Ser 100, Asn 101, Ser 177, Thr 178, Ile 179
2	Cyclamin (saponin)	−28.10		H-bond: Ser 100 (×2), Asn 101, Asp 176, Thr 178 Van der Waals: Asn 93, Asn 95, Asn 98, Ile 179
3	Amaranthine	−21.42		H-bond: Asn 95, Asn 98, His 173 (×2) Pi-Pi: Tyr 174 Van der Waals:Lys 97
4	Alliin	−18.53		H-bond: Ser 100 (×2) Pi-Pi: Asp 176 Van der Waals: Asn 95, Asn 98, Asn 101, Ile 179 Unfavorable: Asp 176
5	Quercetin-3-glucoside	−17.59		H-bond: Asn 95, Asp 176, Thr 178 Van der Waals: Asn 98, Ile 179
6	Aloin	−17.35		H-bond: Ser 100, Asp 176 (×2) Van der Waals: Asn 95, Asn 98, Asn 101, Thr 178, Ile 179
7	Berberine	−15.12		Pi-Pi: Asp 176 Van der Waals: Asn 95, Asn 98, Ser 100, Ile 179
8	Chlorogenic acid	−14.09		H-bond: Asp 176, Thr 178 (×2) Van der Waals: Ile 179
9	Avenanthramide A	−14.03		H-bond: Asn 95, Asn 98, Asp 176 Van der Waals: Ser 100, Ile 179
10	Adiantone	−12.76		H-bond: Asn 101 Pi-Alkyl: Ile 179 Van der Waals: Ala 93, Asn 95, Asn 98, Ser 100, Asp 176
11	Orientin	−11.89		H-bond: Asn 98, Ser 100, Asp 176 Van der Waals: Asn 95, Ile 179
12	Eucryphin	−11.34		H-bond: Ala 93, Ser 100 Van der Waals: Tyr 94, Asn 95, Asn 98, Ser 100, Asn 101
13	Lupeol	−11.15		Van der Waals: Ala 93, Asn 95, Asn 98, Ser 100, Asn 101, Asp 176, Ile 179
14	Quercetin	−11.02		H-bond: Asn 98, Ser 100, Asp 176 Van der Waals: Ile 179
15	Abrusogenin	−10.47		H-bond:Asn 95, Asn 98
16	Shikonin	−10.25		H-bond: Asn 95, Asn 101 Van der Waals: Ala 93, Asn 98, Ser 100
17	Bufadienolide	−10.05		Pi-Alkyl: Ile 179 Van der Waals: Ala 93, Asn 98, Ser 100, Asn 101, Asp 176, Thr 178
18	Nimbin	−8.77		H-bond: Ser 100 (×2), Asp 176 (×2) Van der Waals: Asn 95, Asn 98, Thr 178, Ile 179
19	Genistein	−7.64		H-bond: Asn 98, Ser 100 Van der Waals: Asn 95, Asp 176, Ile 179
20	Solaniol	−7.28		H-bond: Asn 98 Van der Waals: Asn 95, Ser 100, Asn 101, Asp 176, Ile 179
21	E-caryophyllene	−3.25		Van der Waals: Asn 98, Ser 100, Asn 101, Asp 176, Ile 179
22	Limonene	−2.48		Van der Waals: Asn 98, Ser 100, Asp 176, Ile 179
23	S-methyl-L-cysteine	−1.79	No interaction
24	N-acetyl cysteine	−1.05	No interaction

* Color reference: green dotted line indicates H-bond; faint green dotted line indicates van der Waals interaction; orange dotted line indicates Pi-Pi bond; red dotted line indicates unfavorable interaction; purple dotted line indicates Pi-alkyl bond.

Figure 1.

Three-dimensional (3D) interaction diagram of cyclamin (saponin) against human granzyme B (1IAU).

The results of the docking study against human leukocyte elastase are presented in Table 4. It is shown that the reference complexed thiazolidinedione inhibitor displayed C-docker interaction energy equivalent to −33.57 Kcal/mol, while both constituents saponin and amaranthine displayed −48.50 and −47.62 Kcal/mol, respectively. The rest of the compounds displayed in the range of –28.97−10.60 Kcal/mol. The thiazolidinedione ligand inhibited the elastase via four essential H-bonds (Val 59, Asn 61, Asn 62A, and Val 62) and Pi-Pi bonding with Leu 35, Val 62B, and Ala 64. The van der Waals interaction was with Arg 36, Ala 60, and Ile 88. Comparably, saponin was able to inhibit elastase in the same mode, as shown in Figure 2, with better interaction energy. Cyclamin (saponin) bounded to the strategic binding site via two H-bonds with Ala 60 and two H-bonds with Asn 61 and Arg 63, Pi—Pi- bonds with Leu 35, and van der Waals interaction with Arg 36, Gly 39, His 40, Val 59, Val 62, Asn 62 Chain A, Val 62 Chain B, Ile 88, and Glu 90. On the other hand, amaranthine bounded to the binding site via three H-bonds with Ala 60, Asn 61, and Val 62, attractive charge with Arg 36, and van der Waals forces with Leu 35, Val 59, Asn 62 Chain A, and Val 62 Chain B.

Table 4.

Results of molecular modeling study of 23 active constituents against human leukocyte elastase (6F5M) compared to reference complexed ligand.

Serial No.	Compound	(C-Docker Interaction Energy)	2D Interaction Diagram *	Type of Binding
1	Ligand (reference)	−33.57		H-bond: Val 59, Asn 61, Asn 62A, Val 62 Pi-Pi bond: Leu 35, Val 62B, Ala 64 Van der Waals: Arg 36, Ala 60, Ile 88
2	Cyclamin (Saponin)	−48.50		H-bond: Ala 60(×2), Asn 61, Arg 63 Pi-Pi bond: Leu 35 Van der Waals: Arg 36, Gly 39, His 40, Val 59, Val 62, Asn 62A, Val 62B, Ile 88, Glu 90
3	Amaranthine	−47.62		H-bond: Ala 60, Asn 61, Val 62 Attractive charge: Arg 36(×2) Van der Waals: Leu 35, Val 59, Asn 62A, Val 62B
4	Chlorogenic acid	−28.97		H-bond: Asn 61, Asn 62A, Glu 90 Pi-sigma: Ala 60 Van der Waals: Val 59, Val 62, Val 62B, Ile 88, Tyr 94
5	Quercetin-3-glucoside	−27.94		H-bond: Asn 61, Asn 62A Pi-lone pair: Asn 61 Pi-Pi: Val 62 Van der Waals: Leu 35, Val 62B
6	Orientin	−26.43		H-bond: Val 59, Asn 61(×2), Asn 62A, Val 62 Pi-Pi: Val 62 Pi-alkyl: Val 62B Van der Waals: Leu 35, Ala 60
7	Abrusogenin	−26.39		H-bond: Asn 62A, Val 62B Pi-alkyl: Val 62B Van der waal: Leu 35, Arg 36, Ala 60, Asn 61
8	Alloin	−24.93		H-bond: Asn 61, Val 62, Asn 62A(×2) Pi-amide: Val 62 Van der Waals: Leu 35, Val 59, Ala 60, Val 62B
9	Avenanthramide A	−24.18		H-bond: Val 62B Van der Waals: Val 59, Ala 60, Asn 61, Val 62, Asn 62A, Arg 63, Ile 88
10	Nimbin	−22.68		H-bond: Val 62, Asn 62A(×2), Val 62B Pi-Alkyl: Val 62B Van der Waals: Val 59, Ala 60, Asn 61, Arg 63
11	Eucryphin	−22.47		H-bond: Ala 60, Asn 62A Pi-lone pair: Asn 61 Pi-alkyl: Val 62 Van der Waals: Leu 35, Val 62B
12	Quercetin	−20.25		H-bond: Ala 60, Asn 61, Asn 62A Pi-amide: Val 62 Van der Waals: Val 62B, Ile 88
13	Shikonin	−19.80		H-bond: Val 59, Asn 61, Val 62B Pi-sigma: Asn 62A Pi-amide: Val 62 Van der Waals: Ala 60, Ile 88
14	Bufadienolide	−18.71		H-bond: Arg 36 Pi-alkyl: Leu 35(×2), Val 62 Van der Waals: Asn 61, Asn 62A
15	Genistein	−18.31		H-bond: Asn 62A Pi-lone pair: Asn 61 Pi-amide: Val 62 Pi-alkyl: Val 62B Van der Waals: Val 59, Ala 60
16	Lupeol	−18.19		H-bond: Ala 60 Van der waal: Leu 35, Asn 61, Val 62, Asn 62A, Val 62B
17	Adiantone	−17.99		H-bond: Arg 36 Pi-alkyl: Ala 64 Van der Waals: Leu 35, Asn 61, Val 62, Asn 62A
18	Solaniol	−17.44		H-bond: Asn 61, Asn 62A, Val 62 Van der Waals: Ala 60, Val 62B
19	N-acetyl cysteine	−17.25		H-bond: Asn 61, Asn 62A (×3) Van der Waals: Val 59, Ala 60, Val 62, Val 62B
20	Berberine	−16.59		H-bond: Val 59, Asn 61, Val 62B Van der Waals: Ala 60, Val 62, Asn 62A
21	Alliin	−15.63		H-bond: Asn 61, Val 62, Asn 62A Van der Waals: Val 59, Ala 60, Val 62B
22	S-methyl-L-cysteine	−14.29		H-bond: Asn 61, Asn 62A, Val 62
23	E-caryophyllene	−11.78		Van der Waals: Val 59, Ala 60, Asn 61, Val 62, Asn 62A, Val 62B
24	Limonene	−10.60		Pi-alkyl: Leu 35 Van der Waals: Asn 61, Val 62, Asn 62A, Ala 64

* Color reference: green dotted line indicates H-bond; faint green dotted line; indicates van der Waals interaction; lemon green dotted line indicates Pi-lone interaction; orange dotted line indicates attractive charge; dark purple dotted line indicates Pi-sigma bond; medium purple dotted line indicates Pi-amide bond; light purple dotted line indicates Pi-alkyl bond; pink dotted line indicates Pi-Pi bond.

Figure 2.

Three-dimensional (3D) interaction diagram of cyclamin (saponin) against human leukocyte elastase (6F5M).

Granzyme B is a serine protease found in the granules of natural killer (NK) cells and cytotoxic T cells. It is involved in inducing inflammation by cytokine release stimulation and also involved in remodeling of the extracellular matrix. Elevated levels of granzyme B are also implicated in various autoimmune diseases, several skin diseases, and type 1 diabetes [225].

On the other hand, human leukocyte elastase (HLE) is a serine proteinase involved in inflammation and tissue degradation. HLE inhibitors are believed to treat a number of diseases, such as emphysema and cystic fibrosis [220].

Natural products can have enzyme inhibitory potential for the management of different disorders [226]. According to the in silico study results, cyclamin, a saponin, is suggested to be a successful constituent for treating most underlying skin diseases owing to its chemical structure that possesses aliphatic rings, richness in oxygen atoms, and the ability to bind effectively with key amino acids of the binding sites of both granzyme B and HLE.

7. Conclusions

Herbs have great potential to treat various kinds of skin problems. Compared to various allopathic drugs, they have a comparatively low cost and can be of great benefit to many patients, especially poor people. Herbs are rich sources of active ingredients and can be a safer and cost-effective method for the management of skin ailments, ranging from rashes to skin cancer. FDA-approved formulas containing natural sources such as honey and biological cellulose are available and aid greatly in the treatment of skin diseases. Different mechanisms are displayed by such phytochemicals, such as inhibition of multiple inflammatory mediators, ranging from NF-κ, TNF-α, IL-1, TXB2, to COX-2. Their mechanism of action was elucidated via molecular modeling studies that were performed on the active sites of two essential proteins: granzyme B, which is a serine protease found in the granules of natural killer cells (NK cells) and cytotoxic T cells; and human leukocyte elastase (HLE), which is a serine proteinase involved in inflammation and tissue degradation. Molecular docking studies have confirmed that phytoconstituents of natural origin have potential beneficial effects on various skin disorders, especially those containing saponin. Owing to the aliphatic chains and structure rich in oxygen atoms, cyclamin saponin was able to display a comparable and stable complex with both enzymes. C-docker interaction energy expressed by saponin was −28.10 Kcal/mol for granzyme B and −48.50 Kcal/mol for HLE. Saponin bounded to granzyme B similarly to complexed reference via two H-bonds with Ser 100 and three H-bonds with Asn 101, Asp 176, and Thr178. It displayed van der Waals force attraction with Asn 93, Asn 95, Asn 98, and Ile 179, while it bounded to the strategic binding site of HLE via two H-bonds with Ala 60 and two H-bonds with Asn 61 and Arg 63, Pi—Pi- bonds with Leu 35, and van der Waals interaction with Arg 36, Gly 39, His 40, Val 59, Val 62, Asn 62 Chain A, Val 62 Chain B, Ile 88, and Glu 90.

List of Abbreviations

DNA	Deoxyribonucleic acid
UV	Ultraviolet radiation
NF-κB	Nuclear factor-kappa enhancer binding protein
TNF-α	Tumor necrosis factor alpha
C3b	Complement component 3
NO	Nitric oxides
IL-$1\beta$	Interleukin 1 beta
TXB2	Thromboxane B2
COX-2	Cyclooxygenase-2
FDA	Food and Drug Administration
BC	Bacterial cellulose
PC	Plant cellulose
NK	Natural killer
HLE	Human leukocyte elastase

Author Contributions

Conceptualization, A.N.B.S. and A.K.; methodology, I.M.F. and N.M.M.; data analysis, N.M.M., I.M.F. and A.N.B.S.; writing—original draft preparation, D.B., P.T.S., N.M.M. and I.M.F.; writing—review and editing, A.N.B.S., A.K. and N.M.M. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

All data are provided in this review article.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding Statement

This research received no external funding.