INTRODUCTION:

The immune system plays a critical function in defending the body from harmful microbes. Once active the immune system responds immediately by stimulating immune component cells and producing a variety of cytokines, chemokines, and inflammatory mediators. The system is a target of several medications and herbs known as immunomodulators, which function by achieving immunostimulant (as in the treatment of AIDS) or immunosuppression (e.g., the treatment of autoimmune illness)¹. Since time immemorial, medicinal plants have been utilized almost universally as a source of medicine to change immune systems. Several medicinal plants have been studied for immunomodulatory properties, and they have been shown to have a positive influence on the immune system². CADD's role in the drug identification pipeline is to accelerate the discovery of new lead compounds and optimize their structure for subsequent pharmacological studies. The primary CADD methodologies for molecular de novo design and database mining are discussed. They include molecular docking, de novo design, pharmacophore design, and quantitative structure-activity relationship models. New approaches and perspectives on CADD are discussed³. The article reviews modern computer-aided drug design (CADD) methodologies on the immunomodulatory activity of medicinal plants.

Computational Analysis of Immunomodulatory Effects in Various Medicinal Plants:

1. Rajorshi Sen Gupta et al., 2023 demonstrated the potential of phytochemicals from traditional Unani herbs as inhibitors using machine learning via WEKA. They conducted ADMET studies and molecular docking with Mpro (6lu7 chain A) to assess durability and binding affinity. Twenty-five medicinal plants, such as Ashwagandha and Neem, known for their immunomodulatory properties in Unani medicine, were selected. The study identified promising phytochemicals with immunomodulatory properties that could serve as inhibitors against 6LU7 chain A. Active toxicity elimination was performed using Protox-II software, selecting Acacatechin and Isorhamnetin for autodocking with 6LU7 chain A⁴.

2. Ashish-Suttee et al., 2023 utilized an in-silico approach to identify the immunomodulatory potential of Pimpinella anisum phytoconstituents. They employed AutoDock Vina for protein-ligand interaction analysis, considering small molecule screening at the atomic level. The study included basic docking steps such as ligand selection, protein preparation, ligand optimization, and analysis of active binding sites. Pharmacokinetic parameters were evaluated using SwissADME, and drug-likeness was assessed via Lipinski’s rules. The interaction, between anethole, anisaldehyde, trans anethole cis anethole, estragole, linalool and nitric oxide (NOs) showed varying levels of binding strengths from 9.4, to 5.9kcal/mol. The research indicates that the beneficial components found in Pimpinella anisum could potentially act as agents that modulate the system⁵.

3. Trina Ekawati Tallei et al; 2023 explored how bromelains carbohydrate moiety (CMB) could influence the system using techniques. They used the PASS server to predict CMBs effects. Studied its interactions with inflammatory cytokines through molecular docking. CMB showed connections with receptors displaying the highest affinity for IκBβ/NF κB p65 (10.3kcal/mol). The PASS server indicated that CMB has immune boosting properties. The research proposes CMB as a compound for developing drugs to combat inflammation and immune system issues pending confirmation, through laboratory and animal studies⁶.

4. Asmaa Khairy et al; 2023 carried out research, on how natural plants affect the system using network pharmacology, molecular docking techniques and, in experiments. Apigenin, luteolin, diallyl trisulphide, silibinin, and allicin showed significant C-T interactions, while AKT1, CASP3, PTGS2, NOS3, TP53, and MMP9 were the most enriched genes. Pathways in cancer, fluid shear stress and atherosclerosis, relaxin signalling, IL-17 signalling, and FoxO signalling were the most enriched pathways. Curcuma longa, Allium sativum, Oleu europea, Salvia officinalis, Glycyrrhiza glabra, and Silybum marianum had the highest P-C-T-P interactions. Silibinin, luteolin, and apigenin exhibited strong interactions with various genes. In vitro testing showed comparable results to piroxicam in terms of anti-inflammatory and cytotoxicity effects⁷.

5. Jain et al; 2023 conducted a Docking Study on Piperine with Immune Regulatory Proteins. Piperine is a chemical compound found in black pepper and other spices, and it has been found to have anti-inflammatory and analgesic properties in animal studies. The results of these docking studies demonstrated that Piperine exhibited an excellent interaction with targets such as TNF-α, IL-1β, IL-6, and COX-2. This research provides insight into the development of new compounds for immunomodulation and the management of inflammatory illnesses. However, further research on Piperine and related flavonoids is necessary to assess their safety as a potential immunomodulatory agent⁸.

6. Fatimawali et al; 2022 explored betel leaf-derived compounds as potential immunomodulatory agents for COVID-19 symptom management, targeting proinflammatory cytokines. Gas chromatography-mass spectrometry identified bioactive compounds, which were subjected to PyRx-based molecular docking. Seventeen compounds exhibited superior binding energy compared to control agents, with only one violating Lipinski’s rule of five. ADMET predictions suggested favorable pharmacokinetic properties, indicating potential as drug candidates for COVID-19 treatment, particularly for cytokine storms⁹.

7. Muhammad Ryan Radix Rahardhian et al; 2022 utilized an in silico approach to identify a bioactive compound from Peronema canescens (PC) with potential as an immunomodulatory agent targeting interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Autodock 4 was employed for molecular docking simulations, revealing peronemin C1 as the most promising compound with favorable binding energies and interactions against IL-6 and TNF-α receptors. Lipinski's rule of five confirmed drug-likeness for oral administration. ADMET profiling indicated non-mutagenicity for all compounds except peronemin D1. Peronemin C1 showed significant immunomodulatory potential, demonstrating effective inhibition of IL-6 and TNF-α receptors in silico¹⁰.

8. Snehal Kashid et al; 2022 aimed to identify immunomodulatory phytoconstituents of N. Sativa via in-silico studies, including molecular docking. They used Autodock Vina 1.1.2 and BIOVIA Discovery Studio for docking assessment with proteins 1M48 and 1P9M. Ten active constituents were selected, showing good binding affinities with 1M48 (-4.3 to -7.3 kcal/mol) and 1P9M (-5.2 to -9.8 kcal/mol). In-silico ADME studies indicated better druggability and no cytotoxicity. Nigellamine C was identified as the key immunomodulatory agent¹¹.

9. Praveen Kumar Pasala et al; 2022 studied the immunomodulatory potential of Albizia procera (AP) bark through in vivo and silico approaches. In silico analysis involved assessing the binding affinity of AP bioactive molecules on immune-modified proteins like NFkB P52 and TNF-α. In vivo studies on ethanolic extract of AP bark (EEAP) showed immunomodulatory activity in Doxorubicin-induced immunosuppressive rats. Docking results highlighted compounds like 3-O-[α-L-arabinopyranosyl-(12)-β- → D fucopyranosyl - (16) - 2 - acetamido - 2 - deoxy- β - → Dglucopyranosyl] echinocystic acid and Catechin as potential candidates due to their high binding affinity with NFkB P52 and TNF-α. EEAP treatment led to an increase in total leukocytes, neutrophils, and lymphocytes, and enhanced clearance of carbon particles from circulation in both normal and immunosuppressed rats. Delayed-type hypersensitivity test results indicated a stimulatory response on lymphocytes and other essential cells, enhancing cell-mediated immunity¹².

10. Nurul Qalbiyyah Ma’ruf et al; 2022 investigated bioactive compounds from butterfly pea flowers for their immunomodulatory potential via in-silico analysis targeting TNF-α, IL-1, IL-6, and NF-κB receptors. GC-MS identified 48 compounds in methanol extract and 18 in n-hexane extract. Autodock Vina assessed binding free energies, with ten compounds selected for further analysis. Seven compounds adhered to Lipinski’s rule. Acetic acid, 3-hydroxy-6-isopropenyl-4,8a-dimethyl-1,2,3,5,6,7,8,8aoctahydronaphthalen-2-yl ester exhibited high binding free energy to all receptors, with immunosuppressant activity. Butterfly pea flowers show potential as immunomodulators, containing both immune-stimulating and immune-suppressing compounds¹³.

11. Weiwei Jiang et al; 2022 conducted a study on Litopenaeus vannamei (L. vannamei) heads, extracting immunomodulatory peptides through enzymatic hydrolysis. They identified six peptides with promising immunomodulatory properties. These peptides maintained good immune activity under heat treatment, pH treatment, and in vitro gastrointestinal digestion. Molecular docking analysis indicated that these peptides showed great binding to both toll-like receptors 2 and 4 (TLR2 and TLR4/MD-2), leading to immunomodulation. These findings suggest potential for utilizing discarded L. vannamei heads as food-borne immunomodulators¹⁴.

12. Dr. Igor Schepetkin et al; 2021 studied the immunomodulatory activity of essential oils isolated from Rhododendron (Ericaceae) extracts, specifically from the flowers and leaves of R. albiflorum (cascade azalea). They found significant differences in the chemical composition between flower and leaf essential oils, with flowers mainly composed of monoterpenes and leaves primarily composed of sesquiterpenes. These essential oils and their primary sesquiterpenes were found to induce intracellular Ca2+ mobilization but also inhibited agonist-induced Ca2+ mobilization and chemotaxis in human neutrophils and microglial cells. Reverse pharmacophore mapping suggested potential kinase targets, although not supported by kinase binding assays. These findings offer insights into the immunotherapeutic properties of R. albiflorum essential oils, indicating their potential in modulating innate immune responses, particularly by inhibiting neutrophil migration¹⁵.

13. Dr. Gulmira Özek et al; 2021 isolated essential oils from cones and leaves of eight juniper species in Montana and Kazakhstan, including J. horizontalis, J. scopolorum, J. communis, J. seravschanica, J. sabina, J. pseudosabina, J. pseudosabina subsp. turkestanica, and J. sibirica. They examined the oils' chemical composition and innate immunomodulatory activity, finding similarities and differences compared to previous reports. Some samples, particularly from Kazakhstan, contained high levels of cedrol, unique to three species. These oils and pure (+)-cedrol induced intracellular Ca2+ mobilization in human neutrophils. Pre-treatment with these oils or (+)-cedrol inhibited agonist-induced Ca2+ mobilization in neutrophils and FPR1/2 transfected HL60 cells, suggesting desensitization. Pretreatment with J. seravschanica cone oils or pure (+)-cedrol inhibited human neutrophil chemotaxis to N-formyl peptide. Reverse pharmacophore mapping predicted potential kinase targets for cedrol. Cedrol was identified as a novel neutrophil agonist that desensitizes cells to subsequent N-formyl peptide stimulation¹⁶.

14. Fortuna Dwiningsih et al; 2021 conducted a study on the bioactivity of Andrographolide compound from Andrographis paniculata for immunomodulatory purposes using reverse docking studies. They collected the structures of chemical constituents of Andrographis paniculata (Andrographolide) from published literature and removed water molecules and ligands using PyMOL v1.7.4.5 Software. Molecular docking experiments were performed using PyRx 0.8 software. Physicochemical properties, lipophilicity, pharmacokinetics, and drug-likeness properties of the compounds were predicted using Swissadme. Andrographolide demonstrated greater potential as an immunomodulator compared to Muramyl dipeptide based on its binding affinity and intermolecular interactions. Andrographolide showed a binding affinity of -6.9 with interleukin-2 protein, while Muramyl dipeptide showed a binding affinity of -5.6 with interleukin-2. The AMES test indicated that Andrographolide is not a potential mutagen or carcinogen. Drug-likeness prediction revealed that Andrographolide fulfills the rules of Lipinski, Ghose, Veber, Egan, and Muegge with a 0.55 Bio-availability Score¹⁷.

15. Adekunle Babajide Rowaiye et al; 2020 conducted a study on Natural Killer (NK) cells' cytotoxic potentials triggered by activating receptors. They used computational methods to predict natural compounds' selectivity, specificity, and efficacy for cancer treatment. 1,697 compounds from 82 edible tropical plants were docked against 18 NK cell receptor targets using Python Prescription 0.8, with a docking score cutoff of ≥ -7.0 kcal/mol. Further screening for bioavailability, promiscuity, molecular complexity, and pharmacokinetic properties was done using Swissadme and pkCSM web servers. Ligand similarity and phylogenetic analyses were performed using ChemMine and Clustal Omega web servers, while binding site analyses and bioactivity predictions were conducted with Protein-Ligand Interaction Profiler and Molinspiration web servers. Normal mode analyses were carried out with the CABS-flex 2.0 server¹⁸.

16. Hasnat Noor et al., 2020 developed a computational method targeting COVID-19 human host receptors using curcumin derivatives to mitigate infection and complications. They selected 30 compounds, analyzed drug-likeness parameters, and docked 20 analogs against host receptors, identifying 11 with optimal binding affinity. DFT analysis of five shortlisted derivatives showed promising results. Molecular dynamics simulation of hydrazinocurcumin demonstrated immunomodulatory potential against COVID-19, warranting further in vivo evaluation for drug development¹⁹.

17. Sandeep Waghulde et al; 2020 conducted the cheminformatics analysis to elucidate potential immunomodulatory activity of ten derivatives of Cymbopogon citratus. This research revealed that all compounds obey Lipinski’s rules hence good cell membrane permeability and good bioactivity for different drug targets like nuclear receptor ligands and enzyme inhibitors. Therefore, the authors of the study have on one side proposed the topical application of Cymbopogon citratus derivatives as immunomodulators, on the other side, they have brought out the necessity of structural modifications to the compound to achieve enhanced oral bioavailability that would help in increasing the immunomodulators’ therapeutic potential. Thus, the work exemplifies their value in future advancement of research in pharmacology and its derivatives²⁰.

18. Sharuk L. Khan et al; 2020, did a study on β-sitosterol extracted from Muntingia Calabura Linn. bark extract for immunostimulant, antioxidant and for inhibitory effects against the Receptor Binding Domain (RBD) of SARS-CoV-2 spike glycoprotein through molecular docking. Therefore, exploiting β-sitosterol’s immunomodulatory, antioxidant, and antiviral features, they stressed its application in treating COVID-19 via molecular docking analysis on the RBD. The revealed outcomes of the chemical compound including the binding and interaction capabilities with the specific residues also pointed towards β-sitosterol as an important molecule that can in fact boost the immune system against SARS-CoV-2 and further limit virus entry through ACE-2 receptor binding. Gradation type, consumption of β-sitosterol, phytosterols enhanced immunity, vital to counter COVID-19 pandemic²¹.

19. Chhedi Lal Gupta et al; 2019 used in-silico technique to screen human TLR7 modulators. Using ligand based pharmacophore modeling they were able to identify key molecular features that are important in modulating hTLR7. They then proceeded to screen compounds from the InterBioScreen Natural product database and used several filters such as Lipinski’s rule of five and molecular docking. The compound (3a′S,6a′R)-3′-(3,4-dihydroxybenzyl)-5′-(3,4 dimethoxyphenethyl)-5-ethyl-3′,3a′-dihydro 2′H-spiro[indoline-3,1′-pyrrolo[3,4-c]pyrrole] 2,4′,6′(5′H,6a′H)-trione (CompoundID: STOCK1N-65837) appeared as a strong hTLR7 binder/modulator based on the head docking scores and interacting partners. This was also proven using Molecular dynamics simulation where it provided the result for its stability and how effectively it can bind with the target protein. Therefore, research presented in this study serves the purposes of demonstrating the effectiveness of the use of chemical feature based pharmacophore modelling for designing new TLR7 modulators²².

20. Ying Wang et al; 2019 investigated the molecular level targeting the anti-inflammatory and immunomodulatory participation of Cassane diterpenoids (CAs) in rheumatoid arthritis (RA). They suggest that CA via chemical-similarity-based target prediction, molecular docking and molecular dynamics simulation of CA impacts on 4 signaling pathways including TCR, TLR, VEGF and osteoclast differentiation inflammation and immunomodulation. Also, they addressed the binding modes of CAs with major targets unveiled from proper docking studies. CAs with crucial targets identified through credible docking results²³.

21. Da-Peng Bao et al; 2018 aligned the three-dimensional structure of LZ-8 with that of an FIP of Volvariella volvacea and compared the electrostatic potential of the protein surface in the two proteins and then built a model for the specific electrostatic interaction of LZ-8 dimerization. Moreover, an electrostatic potential map, virtual amino acid mutation analysis identified L10, W12, and D45 as residues that might be contributing to high immunomodulatory activity of the protein. The present results may prove instrumental in developing a novel FIP mutant to tackle autoimmune diseases, thanks to its engineering and construction²⁴.

22. Aditya Ganeshpurkar et al; 2018 conducted a study on exploring the in-silico interaction of hesperidin with some chemokines and inflammatory targets. In this study, hesperidin was docked with TNF-α, IL-1β, IL-6, and NOs. Docking studies revealed the excellent interaction of hesperidin with these targets. The result of this work provided insight into the discovery of novel molecules for immunomodulation and treatment of inflammatory disorders. Additional studies on hesperidin and associated flavonoids are necessary to establish its safety. Hesperidin, can, therefore, be considered a candidate for the development of an immunomodulatory agent²⁵.

23. Mayuri Agarwal et al; 2018 conducted a study to explore role of an important phytoconstituent niaziminin B of Moringa olifera for its immunomodulatory potential through conducting in silico docking studies with various cytokines, viz., IL-1β, IL-2, IL-4, IL-5, IL-10, and Interferon-gamma of Gallus gallus (chicken). The protein sequence of interleukin genes was retrieved from NCBI and 3D structures were predicted through the Swiss Model tool. The 3D structure of niaziminin B was retrieved from Pubchem. Molecular docking studies were performed by using the PatchDock server between the phytocompound and chosen receptors and then these results were analyzed. It was observed that niaziminin B exhibited significant binding affinity with IL-5, IL-1β, IL-4 and IL-2. Thus it could be inferred from the present study that the interaction of niaziminin B with various cytokines play important role in immunomodulatory potential of Moringa oleifera²⁶.

24. Anupam Maurya et al., 2012 conducted QSAR, docking, and in vivo studies on triterpenoids isolated from Eucalyptus tereticornis and Gentiana kurroo for immunomodulatory activity. Ursolic acid (1) and lupeol (2) were subjected to QSAR modeling and docking, with results confirmed through in vivo experiments. Both triterpenoids exhibited immunomodulatory and anti-inflammatory activity comparable to boswellic and cichoric acids but less than levamisole. Docking revealed high binding affinity to human receptors. In vivo studies on female Swiss albino mice showed a significant increase in humoral immune function. Both triterpenoids show potential as immunomodulatory drug-like molecules based on in silico and in vivo data²⁷.

25. M. Ahmed Mesaik et al., 2011 conducted comprehensive in silico and in vitro immunomodulatory studies on Lindelofia stylosa compounds. They evaluated the effects of various isolated compounds on ROS production, T-lymphocyte proliferation, and inhibition of key cytokines (IL-2, TNFα, IL-1β, and IL-4). Molecular docking studies highlighted compounds 5 and 6 as potent IL-2 inhibitors, with compound 5 showing the highest potency among all tested compounds²⁸.

26. Dharmendra Kumar Yadav et al; 2011 conducted QSAR and docking studies on gallic acid derivatives for their immunomodulatory activities. Gallic acid and its derivatives are known for various biological activities, including antioxidant and anti-inflammatory properties. Their QSAR model identified compounds G-4, G-7, G-9, G-10, G-12, and G-13 as possessing immunomodulatory activity, with high correlation coefficients. Molecular docking revealed high binding affinities for INFα-2, IL-6, and IL-4 receptors. Compound G-7 exhibited significant immunomodulatory activity, comparable to levamisole, after screening for oral bioavailability, in silico ADME, and toxicity risk assessment²⁹.

27. Dharmendra K Yadav et al., 2010 developed a QSAR model for the immunomodulatory activity of natural coumarinolignoids, particularly those isolated from Cleome viscose seeds. These compounds were recognized for their hepatoprotective action and were preclinically tested for their immunomodulatory effects. Through QSAR and molecular docking studies, the researchers identified potential immunostimulatory compounds. The QSAR model, developed using forward feed multiple linear regression with a leave-one-out approach, demonstrated a high correlation (R2 = 0.99) and predictive accuracy (RCV2 = 0.96). Key factors correlating with biological activity included dipole moment, steric energy, amide group count, lambda max (UV-visible), and molar refractivity. Docking studies confirmed strong binding affinity to immunomodulatory receptors³⁰.

CONCLUSION:

The immunomodulatory activity of some of the medicinal plants has been investigated by using computational methods like molecular docking, ADMET studies, etc further clinical research has to be conducted to verify the effectiveness and safety of these plants for their potential to treat human ailments.

CONFLICT OF INTEREST:

The author has no conflicts of interest.

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Received on 22.07.2024 Revised on 19.09.2024

Accepted on 08.11.2024 Published on 08.03.2025

Available online from March 12, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(1):69-74.

DOI: 10.52711/2321-5836.2025.00011

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.