Molecular Docking Studies of Plant Compounds to Identify Efficient Inhibitors for Ovarian Cancer


Anwesha Barua, Keerthi Kesavan, Sivaraman Jayanthi*

Computational Drug Design Lab, Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore - 632014, Tamil Nadu, India

*Corresponding Author E-mail:



At present, ovarian cancer is at number seven in the list of the leading causes of death in women and also ranks as the sixth most common type of cancer in the world. Researchers have studied this cancer type and detected high-risk genes and the inhibition of these target proteins will help us stop the progression of cancer. Through in silico studies it is easier to screen  ligands and analyze their interaction with these target proteins. Our study’s objective is to compare and identify the most suitable compound that effectively binds to our target protein and decreases its tumor causing actions and consequently, checks tumor growth. Here, Interleukin-6 is taken as our target protein. For centuries, plants have been used for the treatment of innumerable diseases and in recent years, there has been a growing emphasis on the identification and use of plant derived compounds that can act as potent anticancer agents. Hence in our study, more than 100 natural, plant-derived compounds were taken and screened for their inhibitory properties. The compounds that were screened for docking were first subjected to high throughput virtual screening and by in silico docking; the best inhibitor for the target protein Interleukin-6 was selected. According to our results, the ligand 1, 3, 5-trihydroxy-4-methoxyxanthone showed the lowest binding energy. The analysis of its interaction with the target protein may help us develop newer drugs for treatment against ovarian cancer.


KEYWORDS: Ovarian cancer, Natural compounds, Interleukin-6, Virtual screening, 1, 3, 5-trihydroxy-4-methoxyxanthone.




Cancer constitutes a class of diseases that is characterized by the cells which exhibit abnormal growth and are able to invade and spread to other sites on the body (this is termed as ‘malignancy’). Over 100 different types of cancer have been identified till date. Statistical records show that ovarian cancer contributes to nearly 114,000 deaths in women, every year, thereby being one of the leading forms of cancer in the world today1. Ovarian cancer broadly encompasses any cancerous growth that occurs in the ovary.


Ovarian tumor can be classified into six different entities: serous, mucinous, endometrioid, clear cell, transitional cell and squamous carcinoma2. New findings suggest that the vast majority of primary ovarian cancers are not actually derived from the ovary itself, but can arise from the fallopian tubes and endometrium as well 3. Since it has no symptoms in the initial stages, this disease is generally advanced when it is diagnosed. Currently, cancer treatment may include chemotherapy, radiation, and/or surgery. The low survival rate of women with epithelial ovarian cancer has not undergone any significant change since the introduction of platinum-based treatment over thirty years ago4. Approximately almost half of all the cancer patients receive a platinum drug as a form of chemotherapeutic treatment5 and this has a number of disadvantages. No single agent can be effective against all types of cancer. Moreover, the treatment has proven to be ineffective since the cancer cells can acquire resistance by means of somatic evolution6. There are also a number of side-effects ranging from minor to dose-limiting in toxicity, linked to this kind of treatment7,8. There has been ongoing research to find compounds that can inhibit the proteins that get overexpressed in cancerous patients. The functional relationship between inflammation and cancer is not a novel concept. In 1863, Rudolf Virchow proposed a hypothesis that chronic inflammation provide the sites of origin for cancer9,10,11. Chronic inflammation contributes to tumorigenesis during tumor cell invasion, angiogenesis and metastatic dissemination12. Nowadays, analyzing the presence of inflammatory cells within or surrounding the tumor has become an essential aspect of modern pathology13,14. Among the cytokines involved in inflammation, IL-6 (Interleukin-6) is emerging as a pivotal mediator of carcinogenesis, especially in ovarian cancer and may, subsequently, be a potential therapeutic target15,16. IL-6 is an immunoregulatory cytokine with a broad range of biological activity related to the regulation of inflammation, cell differentiation, cell proliferation, immunodulation, haematopoiesis and oncogenesis15. The protein is secreted by a wide range of cell types including macrophages, fibroblast, endothelial cells, T- and B-lymphocytes, keratinocytes and cancer cells17,18. IL-6 stimulates immune response, itcan penetrate the blood brain barrier and initiate the PGE2 production in the hypothalamus, thereby acting as a mediator of fever. IL-6 is secreted from the ovarian cancer microenvironment, either directly from the ovarian cancer cells or through secondary inflammation19,20. It affects tumor progression, either by directly acting on the tumor cells or by acting on the normal cells in the tumor microenvironment21. The protein induces several pathways leading to tumor proliferation, angiogenesis and chemoresistance22,23 via JAK/STAT-3 signaling in tumor cells21,24,25 and IL-6 receptor alpha trans-signaling on tumor endothelial cells26,27. According to advanced medical research, high levels of IL-6 were observed in the malignant ascites of patients suffering from epithelial ovarian cancer28,29. Ascites refer to the condition where there is abnormal fluid accumulation in the peritoneal cavity which is rich in cytokines, growth factors and chemokines. These promote inflammation, tumor cell proliferation and chemoresistance25. In our research, naturally occurring, plant-derived ligands have been considered as the therapeutic agent since natural products exhibit superior chemical diversity and binding affinities for specific proteins30. They have been in use for many centuries and remain an integral part of the pharmaceutical industry. The secondary metabolites derived from most of the plants have shown anti-microbial, anti-cancer and anti-inflammatory activities31. They are also considered safer to use when compared with synthetic compounds due to their crude properties32. Thus, in recent times, the relevance of plant-based compounds has been gradually and steadily increasing in the pharmaceutical industry. To study the protein-ligand interaction, molecular docking has been performed using Schrodinger’s GLIDE tool in order to obtain the best inhibitor for the target protein. Through the HTVS (High Throughput Virtual Screening) mode, it was possible to accurately screen the selected 114 compounds, which would have otherwise been an expensive, tedious and time-consuming process.



In our current study, the anticancer property of several chemical compounds was investigated by performing docking studies with our target protein IL-6.


Preparation of protein target:

The 3-D coordinates or the PDB file of the target protein IL-6 (186-amino-acid length sequence), 1ALU (resolution 1.90 Å), was obtained from the Protein Data Bank. The receptor was prepared for docking by using Schrödinger ‘Protein Preparation Wizard’. The protein was minimized to get its most stable conformation by the addition of polar hydrogen atoms, assignment of atomic charges and elimination of water molecules that are not involved in ligand binding. Minimization continued until the average root mean square deviation of the non-hydrogen atoms reached a value of 0.3 A°.


Preparation of ligands:

From the Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) Database, we obtained a list of 114 naturally-occurring, plant-derived compounds that can be used for treating ovarian cancer by inhibiting the expression of the target protein IL-6. The .mol files of the ligands were downloaded and the ligands were processed using the ‘LigPrep’ tool from Schrodinger to obtain multiple conformation by the addition and removal of hydrogen atoms.


Binding site analysis:

The SiteMap tool from Schrodinger was used to perform the primary binding site analysis in order to identify the active sites on the grid. These active site pockets are the sites where the ligand will bind to the IL-6 to inhibit its activity. The sites consist of hydrophilic, hydrophobic, donor, acceptor and metal binding domains. The best pocket is selected based on its site score and volume.


Glide or ligand docking:

The grid generated output file was uploaded in order to be used as an input for ligand docking against the protein target IL-6 prepared in GLIDE. HTVS (High Throughput Virtual Screening) mode was adopted. HTVS decreases the number of intermediate conformations throughout the docking funnel as well as the thoroughness of the final torsional refinement and sampling. Flexible docking mode was selected.


All the 114 selected plant derived ligands from NPACT database were optimized to have the minimum potential energy and multiple conformers were generated using LigPrep tool. The ligands were optimized to the required criteria and were evaluated for docking analysis. The 3-D structure of IL-6 (Figure 1) was analyzed and prepared using Protein Preparation Wizard. The protein structure was minimized and the optimized structure was further used for docking analysis against the ligands using Glide software. The grid was set for the receptor (IL-6) using Glide to find the active site. The amino acids present at the selected pocket are: Lys-38, Glu-37, Ala-38, Leu-39, Glu-154, Lys-48, Arg-150, Pro-47, Ser-151, Ser-158, Met-49, Phe-155, Arg-161 and Phe-56. Molecular docking allows us to predict the preferred or favorable orientation of one molecule with respect to another when they are bound to each, forming a stable complex. The docking score allows us to estimate the strength of the non-covalent interactions or the binding affinity between the protein and ligand that have been docked. The binding mode and the stability of the IL6- ligand interactions were evaluated using the Glide tool of Schrodinger Suite. The Glide HTVS mode was used for evaluating the best docked compound. From the docking simulation results, as shown in Table 1, we have inferred that out of the 114 compounds, the 3 compounds:-1,3,5-trihydroxy-4-methoxyxanthone, 23- Hydroxy-3-beta-[(O-beta-D-glucopyranosyl-(1->3)- alpha-L-rhamnopyranosyl-(1->2)-alpha-L-arabino pyranosyl) oxy] lup-20 (29)-en-28-oic acid and Periplogenin-3-O-[beta-D-glucopyranosyl-(1->4)-beta-D-cymaropyranoside have shown the best docking scores of -4.284, -4.028 and -3.779 Kcal/mol respectively. Among them, 1, 3, 5-trihydroxy-4-methoxyxanthone is the  ligand with the best GLIDE score of -4.284 Kcal/mol and with the lowest binding energy. A more negative binding energy indicates stronger binding or higher favorable orientation between our target protein and the ligand. The compound fitting in the active site of IL-6 is illustrated in the Figure 2. The amino acids at the catalytic site of 1, 3, 5-trihydroxy-4-methoxyxanthone have been identified from the 2D interaction diagram as shown in Figure 3. The compound forms three hydrogen bonds with the amino acids MET48, GLU154 and SER158. The compound is having hydrophobic interactions with ALA38, LEU39, PRO47, MET48, PHE56 and PHE155. From these interactions, we can conclude that the compound 1, 3, 5-trihydroxy-4-methoxyxanthone has high binding affinity to IL-6 at its active site. This compound can be further validated through experimental studies.



Figure 1: Protein target IL-6


Table 1: Docking results of the best 3 ligands with IL-6 (showing lowest binding energy)









23-Hydroxy-3-beta-[(O-beta-D-glucopyranosyl-(1->3)-alpha-L-rhamnopyranosyl-(1->2)-alpha-L-arabinopyranosyl)oxy]lup-20(29)-en-28-oic acid







Figure 2: Active site pocket



Figure 3: Interaction of the ligand 1, 3, 5-trihydroxy-4-methoxyxanthone with the target protein in the pocket


Studies have been conducted to determine the interrelation of IL-6 with tumor progression and was found to be a major mediator of inflammation in ovarian cancer. There is pre-clinical evidence that the target protein promotes the survival of tumor cells and enhances their resistance to chemotherapy via JAK/STAT signaling in ovarian cancer cells33. When IL-6 interacts with its receptor, it initiates the signaling cascades through the JAK/STAT pathway and the constitutive activation of STAT 3 has been found to contribute to tumorigenesis in several malignancies34,35,36. It has been shown that the neutralizing anti-IL-6 antibody, siltuximab, inhibited IL-6 signaling in ovarian cancer cells. Though it showed consistent inhibition of tumor growth in two of the experiments that were conducted, it, however, did not reach any statistical significance33. Siltuximab is a chimeric antibody that is FDA approved under the name of Sylvant. It may lower resistance to infection and cannot be administered to people suffering from severe infections. Besides having numerous contraindications, it also comes with many side effects. Our research tried to recognize a potential ligand from the plant-based compounds which could serve as an effective therapeutic drug against IL-6. Being a natural product, it would serve as a safer alternative. Unlike the humanized chimeric antibody, it would be comparatively less expensive and more affordable. In our experiment, the binding conformation of each ligand into IL-6 is determined and the one with the lowest binding energy out of all the conformations is generated. Lower the energy score, better the protein-ligand binding affinity. Among the 114 plant-based natural compounds analyzed, the ligands given in the table 1 have the lowest GLIDE scores, thereby, showing the best protein-ligand interaction. Among the three, 1, 3, 5-trihydroxy-4-methoxyxanthone has the lowest energy score of -4.284. Weak molecular interactions play an important role in energetically stabilizing a ligand in the ligand binding pocket of the protein. Studies have demonstrated that both optimized hydrogen bonding and hydrophobic interactions stabilize the ligand at the active site and influence the binding affinity and drug efficacy37. It has been demonstrated that an increase in the number of hydrophobic atoms in the active core of the protein ligand interface can accentuate the biological activity of the drug molecule37. In fig. 3, the amino acids that are present in the active site of the target protein IL-6 can be viewed. It can be observed that within the pocket, the ligand, 1, 3, 5-trihydroxy-4-methoxyxanthone, forms three hydrogen bonds with the following amino acids:- Methionine (49th residue), Glutamate (154th residue) and Serine(158th residue) present in the active site of IL-6. The intermolecular H-bonding between the ligand and protein helps in stabilizing the protein-ligand complex that is formed. Hence, greater the number of hydrogen bonds, greater the stability of the complex and lower the binding energy. The resultant ligand, 1, 3, 5-trihydroxy-4-methoxyxanthone (which is also known as Daphnifolin), can be obtained from the stem and bark extracts of Mesuadaphnifolia38, a tree endemic to Peninsular Malaysia as performed by Ee et al, 2006.



For centuries, plants have been an important source of medicine. In recent times, they have played an important role in providing new, affordable and effective anti-cancer drugs. With new research, new proteins which are associated with tumor progression have been identified and by the help of high throughput screening, it is possible to select compounds that can be effectively used as potential therapeutic drugs against IL-6. Studies have shown that IL-6 is associated with autocrine cytokine system in ovarian cancer cells which involves the co-regulation of cytokines like TNF-α and IL-1β, CCL2, CXCL12 and VEGF. Also, studies have also determined that IL-6 shows paracrine action on angiogenesis in the tumor microenvironment33. The compound that we have identified, 1, 3, 5-trihydroxy-4-methoxyxanthone, has the highest binding affinity with our target protein IL-6 involved in cancer progression. 1D and 2D NMR spectral data have been used for the characterization of the compound structure from Daphnifolin38. As stated earlier, it can be extracted from Mesuadaphnifolia. Till now, no extensive study has been carried out with the tetraoxygenatedxanthone compound. It can be proposed that 1,3,5-trihydroxy-4-methoxyxanthone can effectively bind to IL-6 to inhibit its binding to the IL-6 receptors present in the ovarian cancer cells. This would reduce its tumor-promoting actions and effectively reduce tumor growth. Pre-clinical examinations can help verify the authentication of our in silico studies and also whether the compound can, indeed, be used as a potential anti-cancer drug for the treatment of ovarian cancer.



The authors thank the management of Vellore Institute of Technology, Vellore for providing the facilities to carry out this work.



The authors declare no conflict of interest.



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Received on 28.06.2017             Modified on 25.07.2017

Accepted on 24.09.2017           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(9): 3811-3815.

DOI: 10.5958/0974-360X.2018.00698.4