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    Article

    In silico Evaluation of Immuno-Modulatory Lead Molecules from Elephantopus scaber Linn. on Pro-Inflammatory Markers TNF-α and IL-1β

    Anu Padinhapurath Abhimannue1★, Betty Kokkatt Poulose2★ Corresponding author

    1. 1Department of Biotechnology, St. Mary’s College, Thrissur, Kerala, INDIA.
    2. 2Department of Botany, Sacred Heart College, Chalakudy, Thrissur, Kerala, INDIA.

    CORRESPONDENCE

    Anu Padinhapurath Abhimannue

    Department of Biotechnology, St. Mary’s College, Thrissur, Kerala, INDIA.

    anuabhimannue@gmail.com

    ORCID: 0000-0002-3367-8809

    Received: 14-08-2025; Revised: 24-10-2025; Accepted: 09-12-2025.

    Volume 18, Issue 2 · pp. 503–510 · PUBLISHED Apr-Jun 2026 · DOI: 10.5530/pres.20260171

    View on Pharmacogn. Res. original site ↗

    ABSTRACT

    Introduction Up-regulated expression of TNF-α and IL-1β is a hallmark in chronic inflammation associated pathological conditions. The World Health Organization has identified chronic inflammatory pathological conditions as a leading threat to human health. Statistics point to alarming data where 6 out of every 10 Americans are having chronic inflammatory pathological conditions. Though various therapeutic strategies targeting TNF-α and IL-1β were developed, consistent reporting on side effects was the major hindrance. Hence, there is a need for newer and better therapeutic molecules targeting pro-inflammatory markers. Objectives In the present study, anti-inflammatory property of phyto-constituents identified from Elephantopus scaber is analyzed for its inhibitory effect on TNF-α and IL-1β through molecular docking. Materials and Methods The chemical components in the bioactive fraction of Elephantopus scaber were identified by UPLC-MS-QTOF and molecular docking was performed with the identified molecules to understand its interaction with pro-inflammatory markers. The 11 ligand molecules were docked with optimized and energy minimized crystal structure of TACE, 2OI0 and IL-1β, 5R8Q. Their binding affinities were compared with Rolipram and Indomethacine - the positive controls. Results The binding affinities of the ligands towards 2OI0 and 5R8Q were analyzed and ranked according to their lower energies. Ligand molecules identified in ES1 was found to have better binding efficacy comparing to Ononin and piperine. Conclusion The molecular docking studies have revealed possible bioactive lead molecules which can be further exploited for developing anti-inflammatory drugs.

    KEYWORDS

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    FULL TEXT

    INTRODUCTION

    Inflammation is the defense mechanism exerted by the immune system against any foreign stimuli including deleterious biological, physical or chemical agents. This mechanism aims to restore cellular homeostasis and resolution of pro-inflammatory conditions. However, a failure in resolving acute state leads to chronic inflammation lasting a prolonged time frame (Chen et al., 2017). Chronic inflammation is manifested by the continuous recruitment of pro-inflammatory cells such as macrophages, lymphocytes, and plasma cells releasing inflammatory cytokines, growth factors, Reactive oxygen species, and enzymes, thus contributing to the progression of tissue damage and fibrosis. IL-1β and TNF-α are the key cytokines that orchestrate chronic inflammatory responses (Jacob et al., 2018, Pahwa et al., 2024).

    TNF-α performs a cascade of events leading to the perpetuation of chronic inflammation. TNF-α activates leukocyte adhesion molecules subsequently triggering immune cell infiltration manifested in various pathological conditions (Mohan et al., 2021, Megha et al., 2021). Up-regulation of TNF-α in COPD patient is reported to alter alveolar structure via pleural thickening, and disfiguring chest and lung cavity volumes (Hipolito et al., 2024). Over-expressed TNF-α has been evident in several autoimmune diseases like RA, Psoriatic arthritis and IBD. Over-expressed TNF-α can activate synovial fibroblasts, followed by inducing over-expression of MMP, ultimately resulting in bone and cartilage destruction in RA (Jang et al., 2021). IL-1β, mainly secreted by macrophages and mast cells, is tightly associated with immunomodulation leading to disease progression (Ren et al., 2009). Increased concentration of IL-1β in plasma and synovial fluids is a characteristic feature of Rheumatoid arthritis (Kay et al., 2004). Over-expression of IL-1β is reported to be a hallmark in atherosclerosis, where it induces endothelial cells activation, development of atherosclerotic plaque and invasion into blood vessels (Mai et al., 2020). IL-1β activates the release of other cytokines resulting in airway inflammation in COPD. Release of IL-8 and IL-6 in bronchial epithelial cells, and IL-6 and IL-17 in bronchoalveolar lavage fluid results in neutrophil recruitment and consequently alveolar dysfunction (Zou et al., 2017). Role of IL-1β and TNF-α have been implicated in neuroinflammation resulting in neurodegeneration in Parkinsons Disease (Leal et al., 2013).

    The World Health Organization has identified chronic inflammatory pathological conditions as a leading threat to human health. Statistics point to alarming data where 6 out of every 10 Americans are having chronic inflammatory pathological conditions (Pahwa et al., 2024). Recent evidence points out that chronic inflammation is connected with renal dysfunction, hepatic failure, diabetes, cancer etc. Statistics also point out that 62% of deaths around the globe is due to these diseases alone (Du et al., 2015). Hence, therapeutic strategies targeting pro-inflammatory markers become the focus in managing the present scenario.

    Though PDE4 inhibitors targeting TNF-α production (Rolipram, Cilomilast and Roflumilast) were developed, FDA prevented its commercialization due to side effects like nausea and gastrointestinal problems. Another class of components like adalimumab, certolizumab, golimumab with a modus operandi of competitive antagonism on the TNF-α receptor was also not successful. It exhibited injection site reactions on short term usage and risks of lymphoma on long term usage (Abhimannue et al., 2016). Therapeutic strategies utilizing IL-1 blockers, including IL-1 receptor antagonist (Anakinra), were also developed (Kay et al., 2004). However, side effects like fever, injection site reactions, anorexia, hypotension, and opportunistic infections had led to the limited and cautious usage of drugs (Dinarello et al., 2013, Abdesselam et al., 2010, Imazio et al., 2021).

    With an increasing prevalence of chronic inflammatory pathological conditions and consistent reporting on side effects of current anti-inflammatory drugs, there is a need for newer and better therapeutic molecules targeting pro-inflammatory markers. Medicinal plants as a whole or its different parts have been reported to possess anti-inflammatory compounds that can target multiple points in inflammatory response pathways. Research elucidating the mechanism of action by these natural anti-inflammatory components also remains a lacuna (Dar et al., 2016). In the present study, in silico evaluation of immuno-modulatory lead molecules from Elephantopus Scaber Linn on pro-inflammatory markers TNF-α and IL-1β is conducted.

    MATERIALS AND METHODS

    UPLC MS Q-TOF analysis of E. scaber bioactive fraction, ES1

    Chromatographic separation of components in the crude methanolic extract of E. scaber has been already published by Abhimannue et al., 2017. Thebioactive fraction of E. scaber, ES1 was also analyzed as per the same paper. The accurate mass obtained from the UPLC MS Q-TOF was compared with the data from chemspider for the confirmation of the compound and structure.

    Ligand preparation

    3D structures of all the ligand molecules identified through UPLC MS Q-ToF analysis were built with ChemSketch software developed by Advanced Chemistry Development, Inc. (ACD/Labs). The structure of positive control, Rolipram and Indomethacine were identified from ChemSpider database (http://www.chemspider.com/). All these structures were subsequently converted to pdb format using the Open Babel software (Open Babel, version 2.3.2, http://openbabel.org (accessed 20.03.2015) for virtual screening.

    ADME prediction of the ligands

    The determination of ADME properties and drug likeness of the ligands is an important parameter to be looked upon and was determined using Molsoft online molecular property calculator (http://molsoft.com/mprop/).The numbers of hydrogen donors and acceptors, rotatable bonds, total polar surface area etc was predicted. The percentage of absorption was calculated using equation: % ABS = 109 – (0.345 × TPSA) (Zhao et al., 2002).

    Preparation of protein structure

    The protein crystal structure of TNF-α Converting Enzyme (TACE) and IL-1β with RCSB PDB ID - 2OI0 and 5R8Q was retrieved from Protein Data Bank (http://www.rcsb.org/pdb/). Prior to docking, the receptors were subjected to protein optimization via removing all heteroatoms and energy minimized with Swiss-Pdb Viewer version 4.1.0 (http://www.expasy.org/spdbv/). The protein optimization and energy minimization brings down the energy of macromolecules to a lower level as seen in the native cellular environment; by reducing the sterric clashes and bringing in more orientations that are similar to the theoretical true binding mode. However, Zn2+ - the co-factor of TACE along with its connectors were retained in the structure of the receptor, as they play an important role in its functioning (Rao et al., 2007).

    Docking

    Autodock 4.0 was performed to understand the interaction between pro-inflammatory markers like TNF-α and IL-1β with ligand molecules identified in ES1. A default grid spacing of 0.375 Å with its grid points set to 60 Å each in X, Y and Z coordinates was created with AutoDock 4 to analyze ligand-receptor interaction. For 2OI0, TNF-α Converting Enzyme (TACE) the active site bound to the competitive inhibitor, aryl sulfonamide was chosen for docking and grid box was centered on the X, Y and Z coordinates of amino acid residue VAL 402 (A) at 43.470, 26.765 and 8.236. For IL-1β, 5R8Q the active site bound to the inhibitor, 1-Methyl-N-{[(2s)-Oxolan-2-Yl]Methyl}-1h-Pyrazole-3-Carboxamide was chosen for docking. The grid box was centered on the X, Y and Z coordinates of amino acid residue TYR (A) at 39.666, 1.048 and 71.207.

    For each ligand, a docking experiment consisting of 10 simulations was performed using Cygwin64 Terminal and the outputs were exported to Discovery Studio 4.1 Client for visual inspection of the binding modes and interactions.

    RESULTS

    UPLC MS Q-TOF analysis of E. scaber bioactive fraction, ES1

    Eleven molecules were identified from the bioactive fraction of E. scaber methanolic extract by UPLC MS QTOF and were selected as ligands for the study. It included Methylumbelliferone, Hydroxydihydrobovolide, Lysine theophylline, Ononin, Alismorientol A, Lotaustralin, 2-amino 4-(4-phenylpiperazino)-1,3,5-triazine, Phytosphingosine, Chamazulene, Ethyl oleate, and Piperine. This data aligns with a previous report where bioactive components of crude extract have been published.

    ADME prediction of the ligands

    In the present study 11 molecules identified from ES1, the bioactive fraction of E. scaber extract were screened with pro-inflammatory molecules like TACE, 2OI0 and IL-1β, 5R8Q taken as specific protein targets. The ligand molecules were analyzed for its molecular properties, drug likeness, percentage of absorption and violation to Lipinski’s rule of five, prior to docking (Table 1). The rule states that the Molecular Weight (MW) of the ligand should be ≤ 500, the Hydrogen Bond Acceptor (HBA) and Donor (HBD) groups in the ligand should be ≤ 10 and 5 respectively and mol log P value; which is the partition coefficient of the component in water: octan-1-ol system ≤ 5 (Lipinski et al., 2001).

    Table 1: Physico-chemical properties of the ligands.
    Sl. No.ComponentMWHBAHBDM LogPM LogSMVN-SCDLTPSA (A0)2% ABS
    1Methylumbelliferone176.05311.81-2.6192.40-0.4338.2695.8003
    2Hydroxyl dihydrobovolide198.13312.4-1.36246.391-0.6139.0395.5347
    3Lysine theophylline326.1776-2.8-1.28316.4510.73124.6765.9889
    4Ononin430.13940.7-4.54403.495-0.02108.2671.6503
    5Alismorientol A272.2441.61-0.8327.666-0.5962.2187.5376
    6Lotaustralin261.1274-1.94-0.99256.226-0.1296.475.742
    72-amino-4-(4-phenylpiperazino)-1,3,5-triazine256.14321.59-1.8228.680-0.2257.4589.1798
    8Phytosphingosine317.29453.51-5.35353.163-1.5970.2584.7638
    9Chamazulene184.13004.76-5.01222.280-1.160109
    10Ethyl oleate310.29207.98-6.67388.60-0.7820.67101.8689
    11Piperine285.14303.96-4.88328.920-0.0233.4797.4529
    12Rolipram275.15312.54-2.96292.9610.8747.5692.592
    13Indomethacine357.08414-4.57340.5800.9151.3191.298

    Other parameters like Topological Polar Surface Area (TPSA), % absorption, No: of stereo-centres and drug likeness score are also considered. TPSA defined as the sum of surfaces of polar atoms in a molecule, predicts the drug transport properties and cell permeation properties. The recommended TPSA values are < 140 A˚ and 90 A˚ for cell permeation and blood-brain barrier respectively. The percentage of absorption is calculated from TPSA value using equation: % ABS = 109 – (0.345 × TPSA). It is observed that with increase in TPSA value, the percentage of absorption was found to be decreased. Less No: of Stereo-Centres (N-SC) suggest that upon binding the ligand undergoes only a slight conformational change. The Drug Likeness (DL) is a qualitative concept which predicts the likeness of a molecule to a drug.

    All ligands except lysine theophylline (HBD > 5) and ethyl oleate (Mol Log P > 5) were found to follow all parameters of Lipinski’s rule of five. The drug likeness score of the ligand molecules were comparable with positive control –Rolipram and Indomethacine.

    Molecular docking of bioactive components from ES1 with TACE, 2OI0 and IL-1β, 5R8Q

    The 11 ligand molecules identified in ES1 were docked with optimized and energy minimized crystal structure of TACE, 2OI0 and IL-1β, 5R8Q. The binding affinities of the molecules with TACE, 2OI0 were compared with Rolipram - the positive control. Ononin was found to have better binding efficiencies than Rolipram. The binding affinities of the molecules with IL-1β, 5R8Q were compared with Indomethacine. However, it was found that piperine from ES1 have better binding efficiency.

    The binding affinities of the ligands towards 2OI0 and 5R8Q were analyzed and ranked according to lower energies as shown in the Tables 2 and 3. The docked poses of the positive control and the molecule with the best binding efficiency are presented in the figures (Figures 1 to 4).

    Figure 1: The docked pose of Rolipram, the positive control at the active site of TACE, 2OI0. The key amino acids interacting with the ligand is labeled in the figure and (B) Represents the protein-ligand interactions. Different bindings are shown in various colors. : Conventional hydrogen bond, : Carbon hydrogen bond, Pi- alkyl interaction, Attractive charge, Pi-Cation and : Pi-Pi stacked.
    Figure 2: The docked pose of Ononin at the active site of TACE, 2OI0. The key amino acids interacting with the ligand is labeled in the figure and (B): Represents the protein-ligand interactions. Different bindings are shown in various colors. : Conventional hydrogen bond, : Carbon hydrogen bond, Pi- alkyl interaction, Pi-Anion, Pi-cation, : Pi-Pi T-shaped and : Pi-Sigma.
    Figure 3: The docked pose of Indomethacin at the active site of IL-1β, 5R8Q. The key aminoacids interacting with the ligand is labeled in the figure and (B): Represents the protein-ligand interactions. Different bindings are shown in various colors. : Conventional hydrogen bond, : Van der Waals interaction, : Water hydrogen bond.
    Figure 4: The docked pose of Piperine at the active site of IL-1β, 5R8Q. The key amino acids interacting with the ligand is labeled in the figure and (B): Represents the protein-ligand interactions. Different bindings are shown in various colors. image2: Conventional hydrogen bond, image10: Van der Waals interaction, image10: Water hydrogen bond, image4 Pi- alkyl interaction, image3: Carbon hydrogen bond and image8: Pi-Sigma.
    Table 2: The binding energy of the 11 ligands identified in ES1, the bioactive fraction of E. scaber towards TACE, 2OI0 along with the list of amino-acids interacting with the protein. # Binding energies are expressed as mean ± S.D., of 10 different docking poses.
    Ranking as per binding affinityLigandMin. binding energy (Kcal/mol)Key protein ligands interaction
    Positive controlRolipram-9.134 ± 0.0052GLU A: 406, HIS A: 405, VAL A: 402, 434, LEU A: 401, TYR A: 436, ASN A: 447, Pi- Anion interaction with Zn.
    1Ononin-10.917 ± 0.038PRO A:437, VAL A:402, TYR A:436, LEU A:401, 350, ASN A:447, ALA A:439, GLU A: 406, GLY A:349, HIS A:415, Pi- Anion interaction with Zn.
    2Piperine-10.021 ± 0.2164LEU A: 401, 348, VAL A: 434, 440, 402, ASN A: 447, TYR A: 433, 436, LYS A: 432, ALA A: 439, ILE A: 438, HIS A: 405, GLU A: 406, GLY A: 349, THR A: 347, PRO A: 437, Pi- Anion interaction with Zn.
    32-amino-4-(4-phenylpiperazino)-1,3,5-triazine-9.282 ± 0.0249LEU A: 348, 401, GLU A: 406, VAL A: 402, 434, TYR A: 436, ALA A: 439.
    4Alismorientol A-9.21 ± 0.0GLU A: 398, LEU A: 401, 348, ALA A: 439, VAL A: 440, 434, 402, ASN A: 447, LYS A: 432, TYR A: 433, 436, ILE A: 438, HIS A: 405.
    5Ethyl oleate-8.967 ± 0.1607ALA A: 351, 439, GLU A: 406, 398, VAL A: 440, 402, ASP A: 443, LYS A: 397, GLY A: 442, 349, LEU A: 395, 402, 348, 350, SER A: 441, PRO A: 437, PHE A: 347, HIS A: 409, 408, Pi- Anion interaction with Zn.
    6Phytosphingosine-8.865 ± 0.2393HIS A: 409, VAL A: 440, 434, TYR A: 433, ALA A: 439, LEU A: 350.
    7Lotaustralin-8.598 ± 0.0048GLU A: 406, LEU A: 348, 401, VAL A: 402, HIS A: 405.
    8Chamazulene-8.048 ± 0.0042HIS A: 405, TYR A: 436, 433, LYS A: 432, VAL A: 440, 434, LEU A: 401.
    5Hydroxyl dihydrobovolide-7.568 ± 0.0929ASN A:447, VAL A:402, HIS A:405
    10Methylumbelliferone-7.140 ± 0.0031LEU A:401, VAL A: 434, 402, HIS A:405
    11Lysine theophylline-4.350 ± 0.0031LEU A:401, ALA A:439, TYR A:433, 436, HIS A:405
    Table 3: The binding energy of the 11 ligands identified in ES1, the bioactive fraction of E. scaber towards IL-1β, 5R8Q along with the list of amino-acids interacting with the protein. # Binding energies are expressed as mean ± S.D., of 10 different docking poses.
    Ranking according to the binding affinityLigandMin. binding energy (Kcal/mol)Key protein ligands interaction
    Positive ControlIndomethacine-8.628 ± 0.4413VAL A: 41, GLU A: 64, LYS A: 63, LYS A: 65.
    1Piperine-9.826 ± 0.7913LYS A: 65, GLU A: 38, MET A: 20, VAL A: 19, SER A: 21, LYS A: 27, ASN A: 129, LEU A:29.
    1Ononin-9.002 ± 0.3817LEU A: 69, LEU A: 26, MET A: 20, LYS A: 65, VAL A:41.
    2Alismorientol A-8.972 ± 0.4695PRO A: 131, LEU A: 69, LEU A: 80, GLN A: 81, LEU A: 82, VAL A:132, TYR A: 24, GLU A: 25, LEU A: 26
    3Ethyl oleate-8.552 ± 0.1254LYS A: 63, GLU A: 64, MET A: 20, LYS A: 65, VAL A: 41.
    5Lotaustralin-8.001 ± 0.0544SER A:123, MET A:44, GLN A: 141, ALA A:28, LEU A:18, SER A:17
    62-amino-4-(4-phenylpiperazino)-1,3,5-triazine-7.595 ± 0.5332GLU A: 64, LYS A:77, ARG A:98
    7Phytosphingosine-7.330 ± 0.1824LYS A:27, MET A: 20, ALA A:28, LEU A:18, SER A: 17.
    8Hydroxyl dihydrobovolide-6.951 ± 0.1508SER A: 123, SER A: 43, ASN A:7, GLN A:141, MET A:44
    9Chamazulene-6.654 ± 0.0870MET A: 20, LYS A: 65, VAL A:19,, GLN A: 38.
    10Methylumbelliferone-6.349 ± 0.0870LYS A:27, MET A:20, ALA A:28, LEU A:18, SER A:17
    11Lysine theophylline-4.006 ± 0.1203GLN A: 39, LEU A: 29, GLN A:126, SER A: 17, VAL A:40

    DISCUSSION

    Monocytes are reported to be critical effectors and regulators of inflammation. These cells respond to a variety of stimuli like pathogens, antigens, tumors etc. and are responsible for the secretion of pro-inflammatory cytokines (Geissmann et al., 2010). Excessive infiltration and accumulation of monocytes are strongly associated with numerous pathological conditions like atherosclerosis (Tabas et al., 2017), bronchial asthma (Tanizaki et al., 1982), ischemic stroke, autoimmune multiple sclerosis and infectious encephalitis (Yang et al., 2014), intraplaque angiogenesis and tissue destruction (Woollard et al., 2010, Pamukcu et al., 2010).

    The importance of TNF-α and IL-1β has been demonstrated in the destructive process of chronic inflammation related diseases like rheumatoid arthritis. These pro-inflammatory molecules consecutively activate tissue destroying MMPs and induce osteoclastogenesis through the stimulation of Receptor Activator of Nuclear factor-kB Ligand (RANKL). The synergestic upregulation in IL-1β synthesis by TNF-α has been proposed in chronic inflamed joints of rheumatoid arthritis models (Magyari et al., 2014). Hence, TNF-α and IL-1β are considered as effective therapeutic targets in the treatment of chronic inflammation related pathological conditions. Results from Molecular docking studies reveal the potential of bioactive molecule in E. scaber in significant inhibition of production of TNF-α and IL-1β.

    CONCLUSION

    The present study had highlighted the anti-inflammatory potential of E. scaber extract with respect to inhibition of pro-inflammatory cytokines production. The bioactive fraction of E. scaber methanolic extract had resulted in eleven ligand molecules with druggability features for inhibition of TNF-α and IL-1β production. Molecular docking had lead to some promising agents which can be further exploited for anti-inflammatory therapeutic effect.

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    Abhimannue, A. P., & Poulose, B. K. (2026). In silico Evaluation of Immuno-Modulatory Lead Molecules from Elephantopus scaber Linn. on Pro-Inflammatory Markers TNF-α and IL-1β. Pharmacognosy Research, 18(2), 503–510. https://doi.org/10.5530/pres.20260171