|Year : 2022 | Volume
| Issue : 1 | Page : 40-47
In silico screening of identified phytochemicals from the leaf of Cipadessa baccifera (Roth.) miq. for its anti-psoriatic activity
Minautee R Patel1, Amit Patel2, Mukeshkumar Nariya2, Rabinarayan Acharya1
1 Department of Dravyaguna, Institute of Teaching and Research in Ayurveda, Jamnagar, Gujarat, India
2 Pharmacology Laboratory Institute of Teaching and Research in Ayurveda, Jamnagar, Gujarat, India
|Date of Submission||04-Mar-2021|
|Date of Decision||29-Jun-2021|
|Date of Acceptance||04-Jul-2021|
|Date of Web Publication||19-Mar-2022|
Minautee R Patel
Department of Dravyaguna, Institute of Teaching and Research in Ayurveda, Jamnagar - 361 008, Gujarat
Source of Support: None, Conflict of Interest: None
Introduction: Psoriasis (kitibha) is characterized by chronic inflammation and epidermal hyperplasia where mast cells and tryptase are activated with related form of cytokines. Cipadessa baccifera (Roth.) Miq. (Meliaceae family) is an ethnomedicinal plant reported for its anti-psoriatic tribal claim. In the present study, in silico docking study was planned for proven clinical use of C. baccifera in psoriasis with identified phytoconstituents. Methods: Eight identified well-known phytochemicals from the leaf of C. baccifera were used. The molecular docking studies were performed using iGEMDOCK2.1. Drug likeness of the compounds was predicted using Swiss ADME while in silico toxicity studies were performed using ProTox-II online tool. Results: All of retrieved eight phytoconstituents of C. baccifera possesses drug likeness properties. Phytoconstituents are nontoxic in nature and showing bioavailability, having significant inhibitory activities on validated anti-psoriatic targeted proteins, 2ZEB (Human Mast Cell Tryptase) and 2AOT (Histamine methyltransferase). Conclusion: The results of present study suggest the potential clinical role of C. baccifera in psoriatic patients and thus, proved the traditional claim through in silico docking study.
Keywords: Cipadessa baccifera, ethnomedicinal, in silico, phytochemicals, psoriasis, toxicity
|How to cite this article:|
Patel MR, Patel A, Nariya M, Acharya R. In silico screening of identified phytochemicals from the leaf of Cipadessa baccifera (Roth.) miq. for its anti-psoriatic activity. J Ayurveda 2022;16:40-7
|How to cite this URL:|
Patel MR, Patel A, Nariya M, Acharya R. In silico screening of identified phytochemicals from the leaf of Cipadessa baccifera (Roth.) miq. for its anti-psoriatic activity. J Ayurveda [serial online] 2022 [cited 2022 Nov 29];16:40-7. Available from: http://www.journayu.in/text.asp?2022/16/1/40/339989
| Introduction|| |
Psoriasis is an agonizing skin disease, classified under papulosquamous disorder with a morphological feature of scaly papules and plaques. It is characterized by chronic inflammation and epidermal hyperplasia, where numerous inflammatory and immune cells are present simultaneously, and then, mast cells have become visible in this complex cellular and molecular network. The presence of mast cells in dermis initiates the activation of psoriasis. Mast cells are present inside the epidermal lesion, and psoriatic lesion is specific feature of psoriasis.,, In psoriatic plaque, increased amount of interstitial histamine suggests the mast cell activity and its degranulation., Mainly, T-lymphocyte-mediated immune response is responsible or psoriasis.
There is limited scope in the modern medicine for the treatment of psoriasis. Various synthetic or semisynthetic preparations are available for topical and systemic applications but have certain side effects. In Ayurvedic classical literature, very effective treatment modalities are given for the treatment of Kustha (Skin). Various types of skin diseases are considered under kustharoga, Psoriasis is mostly comparable with Ekakustha, kitibhakustha, and Sidhmakustha which are categorized under Kshudrakusthas and mahakustha. Many medicinal plants and its formulations are widely used to treat skin disorders. Cipadessa baccifera (Roth.) Miq. belongs to Meliaceae family is an ethnomedicinal plant and used in tribal community to treat psoriasis. The paste of leaf, bark, and root of C. baccifera is topically used for skin disorders and also ground with leaf of Lantana wightiana for topical application in psoriasis.,, Paste of stem bark and tender branches of C. baccifera are used in allergic condition. Fresh leaves grounded, mixed with sesame oil used externally in skin disease.
Bioinformatics and systems biology approaches are becoming important to study the therapeutic potential of medicinal plants. In silico approaches have been widely recognised to know the molecular effect of its isolated compounds against targeted proteins. It may useful in new drug discovery and drug development based on reverse Pharmacology approach. Although many traditional claims on C. baccifera for its anti-psoriatic activity, no scientific data available after detail review. Thus, in silico docking study was planned in the present study for proven clinical use of C. baccifera in psoriasis with identified phytoconstituents.
| Materials and Methods|| |
The compounds reported in previous study by different analytical methods from the leaves extract of C. baccifera were used in the present study [Table 1]. The three-dimensional (3D) structures of the eight compounds (ligands) retrieved from database of PUBCHEM [Figure 1]. These compounds directly used for docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies.
Preparation of proteins
Tryptase is an enzyme released along with histamine and other chemicals from activated mast cells. In psoriasis, release of tryptase supports the significant role of innate immunity. In the primary stage of plaque development, it is believed that the activation of innate immune system plays a vital role in which mast cells contribute to producing interleukin-22 (IL-22) and IL-17., Thus, crystal 3D structures of proteins 2ZEB (Human Mast Cell Tryptase) and 2AOT (Histamine methyltransferase) (PDB id: 2ZEB and 2AOT) were selected and downloaded from online data bank of protein (https://www.rcsb.org) in the PDB format. Structure of proteins 2ZEB and 2AOT was evaluated based on of Ramachandran plot using RAMPAGE. Energies of proteins, polar molecule of water and hydrogen charges were minimized, removed and added, respectively. Finally, 3-D structures of proteins saved in PDB format and directly used for preliminary screening and analysis for docking by using iGEMDOCK.
Molecular Docking and postanalysis and/or result of the molecules were done in iGEMDOCK Software with the protein targets 2ZEB and 2AOT. The targets of binding sites were prepared, and the compound with reduced energy was imported. After the docking ligands were analyzed and selected for iGEMDOCK score. The 8Å (Angstrom) was target of the binding site. The empirical scoring function of iGEMDOCK was estimated as: Fitness = vdW + Hbond + Elec.
In silico prediction of activity spectra for substances
Phytochemicals, namely Cipadesin J, Cipadesin K, CIpadesin L, Cipadesin M, Cipadesin N, Cipadesin O, Cipadesin P, and Ciparesin B reported in C. baccifera are having antipsoriatic activity. The compounds were predicted with the help of computer program prediction of activity spectra for substances (PASS) online server. The predicted activity spectrum of the compounds marked as probable activity (Pa) and probable inactivity (Pi). The ratio of Pa and Pi vary between 0.000 and 1.000. If Pa >0.7, the probability of particular pharmacological action is high and if between 0.5 < Pa < 0.7, probability of particular pharmacological action is less. If Pa <0.5, the compound is unlikely to exhibit pharmacological action but, it may indicate the possibility of getting a new compound.,
In silico ADME and toxicity studies
Pharmacokintetic properties and in silico toxicity studies of compounds were predicted using Swiss ADME and ProTox-II online web server tools, respectively. The toxic effects of test compounds were assessed on specific organ toxicity, carcinogenicity, mutagenicity, cytotoxicity, and class of toxicity.
| Results and Discussion|| |
In the field of computer-aided drug design, molecular docking plays an important role in the new drug discovery and drug development. It includes screening of small molecules by orienting and scoring them according to binding site with the protein. Mast cells are increased in psoriatic lesional skin with tryptase positive. From immunohistochemistry experiments, it was reported that, tryptase is largely found in a layer of dermis, dermis-epidermal junction, and around blood vessels.
In the present study, identified phytoconstituents selected from leaf of C. baccifera with their chemical formula, compound ID and molecular weight as listed in PubChem [Table 1]. Total eight compounds were selected, Cipadesin J, Cipadesin K, CIpadesin L, Cipadesin M, Cipadesin N, Cipadesin O, Cipadesin P, and Ciparesin B from leaf of C. baccifera. Individually, each compound has its own biological prominence and utilities, but in the present study considering the clinical usage of C. baccifera in psoriatic patients, the in silico docking study was planned to assess the role of well-known phytoconstituents on targeted protein involved in psoriasis.
Phytoconstituents from C. baccifera severed as ligands and molecular docking were done with target protein 2ZEB (potent nenopeptide inhibiters of human mast cell) and 2AOT (Histamine methyltransferase). Structure proteins of 2ZEB and 2AOT were described by Ramachandran plot [Figure 2] and [Figure 3]. For 2ZEB protein, it was observed that, 545 (97.3%) residues of the predicted proteins in favored region, 14 (2.5%) in the permissible region and 1 (0.2%) in nonpermissible region. Simultaneously, for 2ZEB protein, it was observed that, 906 (94.4%) residues of the predicted protein in favored region, 50 (5.2%) in permissible region and 4 (0.4%) in nonpermissible region. The protein targets were minimized in energies, polar molecules were removed and H+ and charges added. The 3D structures of proteins obtained were used for in silico docking with phytoconstituents.
In silico predictions of ADME process are used to minimizing the synthesis of compounds to obtain the required biochemical and physicochemical profile. ADMET profile of phytoconstituents plays a crucial role in the discovery of new drug. A ligands must pass through multiple filters to considered as a drug-like properties. “Lipinski rule of five (Ro5)” is work in such manner to filter ligands and scrutinize the drug-likeness of drug candidate and/or properties. As per Lipinski rule, the compound has consist of <5 hydrogen bond donors, <10 hydrogen bond accepters, a molecular weight of <500 Dalton and a partition coefficient log P of <5, in order to be drug-like properties. This is also important for intestinal absorption, bioavailability and blood brain barrier (BBB) permeability, etc. Drug molecule not selected as ligands for docking purpose if not pass the two or more of the Lipinski rule. In the present study, parameters were calculated using Lipinski rule and ADME properties of phytoconstituents of C. baccifera [Table 2]. All the eight bioactive phytoconstituents of C. baccifera found eligible for all the criteria of Lipinski's rule of five for drug likeness therefore selected as ligands.
|Table 2: In-silico absorption, distribution, metabolism, excretion study of phytoconstituents from Cipadessa baccifera|
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Toxicity classes are defined according to the Globally Harmonized System (GHS). Results of in silico toxicity studies shows that all the retrieved molecules were belong to toxicity class 3 and 4 [Table 3], hence as per GHS guideline all compounds found safe.
|Table 3: In-silico toxicity study of phytoconstituents from Cipadessa baccifera|
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The boiled egg model was used for the calculation of pharmacokinetics properties. It allows for spontaneous determination of indirect GI tract absorption (HIA) and crossing of BBB. The white area is denoting for higher chances for passing of ligands through passive absorption in GI tract and the yellow region (yolk) is denoting high probability of penetration in BBB. All eight phytoconstituents C. baccifera are showing passive absorption in the GI tract but not crossing the BBB [Figure 4].
The interactions of eight phytoconstituents of C. baccifera with selected target proteins were identified by performing the in silico docking study. Histamine and tryptase are two important targets in psoriatic disease and if drug inhibits the release of these two targets it may help to control disease condition. Hence, Human Mast Cell Tryptase (2ZEB) and Histamine methyltransferase (2AOT) selected as a target proteins and Phytoconstituents from C. baccifera were tested against these target proteins. The compounds were screened on the basis of binding energy and their interaction with the protein molecules. The binding results suggest the maximum level to the active site. The binding affinity (docking score) for all eight Phytoconstituents form C. baccifera showed significant inhibition of both targeted proteins 2ZEB and 2AOT with Good docking score [Table 4] and [Table 5]. Visualization of 3D interactions and orientation of molecules carried out using PyMol visualization tool [Figure 5] and [Figure 6]. All of eight phytoconstituents from C. baccifera interacted with both validated anti-psoriatic targeted proteins 2ZEB and 2AOT at varying degrees. Molecular interactions of C. baccifera phytoconstituents with various amino acids residues of protein mentioned in [Table 4] and [Table 5].
|Figure 5: Visualization of three-dimensional interactions and orientation of molecules were done using PyMol visualization tool of 2zeb|
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|Figure 6: Visualization of three-dimensional interactions and orientation of molecules were done using PyMol visualization tool of 2AOT|
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Investigation of the docking study revealed that, structural bulkiness and existing polar groups in phytoconstituents from C. baccifera are necessary for favorable interaction across the anti-psoriatic targeted proteins. Physicochemical features of the bioactive phytoconstituents and their interesting binding interactions with selected anti-psoriatic protein targets may use for the advancement of anti-psoriatic drug development.
| Conclusion|| |
All of retrieved eight phytoconstituents of C. baccifera possess drug likeness properties. Phytoconstituents are nontoxic in nature and showing bioavailability, having significant inhibitory activities on validated anti-psoriatic targeted proteins, 2ZEB and 2AOT. The results of present study may suggest the potential clinical role of C. baccifera in psoriatic patients and thus, proved the traditional claim through in silico docking study.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]