In silico approach of compounds in Cissus quadrangularis targeting multiproteins as anticancer agents

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1 Research Article In silico approach of compounds in Cissus quadrangularis targeting multiproteins as anticancer agents C. N. Hemalatha 1, Elancheziyan K 1, D. Pavithra 2, M. Vijey Aanandhi 3 * ABSTRACT Introduction: Cissus quadrangularis (CQ) is a perennial medicinal plant of the family Vitaceae which has been used for various treatments such as anti-inflammatory, anticancer, and antioxidant activity. The objective of this study was to find the G-quadruplex targets, binding energy of CQ biological active compounds, and drug likeliness by in silico techniques for anticancer activity. Metirials and Methods: The targets were retrieved from PDB bank, and plant data compounds are taken from literature survey and chosen seven compounds such as resveratrol, gallic acid, quercetin, stigmasterol, piceatannol, asarone, and luteolin for the study. These compounds are docked using G4LDB Database with the 6 PDB IDs such as 1L1H, 10OK, 2HRI, 3CE5, 3NYP, and 3SC8. Except for stigmasterol, the compounds have been showed good interactions and binding energy with the PDB ID-1L1H. Result and Discussion: From the docking results, four compounds such as resveratrol, quercetin, piceatannol, and luteolin show satisfactory dock score values of about 6.01, 7.14, 6.48, and 7.46, respectively. These compounds are visualized using Discovery Studio 4.1 Visualizer followed by DruLiTo software which satisfies the Lipinski s properties for all the compounds. Conclusion: These results depict the phenolic and flavonoid derivatives having a significant role to design new compounds with these properties for anticancer activity. KEY WORDS: Cissus quadrangularis, G4LDB database, Lipinski s rule, Molecular docking INTRODUCTION Cancer is one of the major diseases and challenging to medicinal system to produce potent and the site-specific anticancer drugs. A vast number of investigation is to find the potent and safer anticancer drugs. As these drugs are more high-priced and possess more side effect, enormous researches being carried out to synthesis a drug with more efficacy and safety profile. [1-3] Rich source of bioactive compounds has played a significant role in these modern days particularly in the medicinal plants and serves as an important target for the discovery of new drugs. Cissus quadrangularis (CQ) is one among the medicinal plant which contains various bioactive compounds, and the plant extracts have been recognized as cancer preventive agents. [4-6] These extracts or the substances will block cell cycle progression and leads to apoptosis. G-quadruplex Access this article online Website: jprsolutions.info ISSN: ligands are formed in tertiary structures of nucleic acids by sequences that are rich in Guanine. Some of the G-quadruplex ligands which interact with the enzymes with the formation of repeated sequences at the end and this process may in turn decrease the activity of the enzyme which leads to cell apoptosis. [7] In this study, we have chosen the potential bioactive compounds from CQ and targeted the G-quadruplex ligands using G4LDB Database. [8] MATERIALS AND METHODS CQ-derived compounds: selected for this study are (a) resveratrol, (b) gallic acid, (c) quercetin, (d) stigmasterol, (e) piceatannol, (f) asarone, and (g) luteolin, and their structures are shown in Table 1. Lipinski s properties such as molecular weight, lop P, and number of hydrogen bond donors and acceptors taken from DruLiTo software for CQ derive plant compounds, and they satisfy Lipinski s rule of five for Drug-likeness. The values of the Lipinski s properties which deviated 1 Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Chennai, Tamil Nadu, India, 2 Department of Pharmacy Practice, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies, Chennai, Tamil Nadu, India, 3 Department of Pharmaceutical Chemistry and Analysis, Vels Institute of Science, Technology and Advanced Studies, Chennai, Tamil Nadu, India *Corresponding author: Dr. M. Vijey Aanandhi, Department of Pharmaceutical Chemistry and Analysis, Vels Institute of Science, Technology and Advanced Studies, Chennai , Tamil Nadu, India. hodpchemistry@velsuniv.ac.in Received on: ; Revised on: ; Accepted on:

2 from Lipinski s rule of five are highlighted in Table 2. All three-dimensional (3D) structures of G-quadruplexes in the database are recorded in RCSB Protein DataBank. The retrieved G-quadruplex complex will be forming a grid box (15 A 15 A 15 A, and grid points with A spacing). Table 1: Compound with the structures RESVERATROL GALLIC ACID QUERCETIN STIGMASTEROL ASARONE PICEATANNOL LUTEOLIN The docking proceeds in two steps. In the first step, the structures transformations and geometry optimization will be performed by Open Babel and Auto Dock Tools from the server end. The second step involves the predefined active site, and it will be calculated by AutoGrid. As the database was assigned by Gasteiger partial charges to the atoms in the ligand as well the calculations are done by AutoDock. The G4LDB database is a unique collection of quadruplex ligands which lead to promising results for drug discovery targeting G-quadruplexes. The module consists of 28 models of G-Quadruplex in which it covers all known binding models reported in RCBS protein bank. The docking process was done by submitting the PDB coordinated of protein and ligand. The G4LDB site can be best viewed by Firefox, Safari, Google Chrome, and Opera in which JavaScript (version >1.7) and Java (version >6) are enabled. The platforms that have been tested and that show stability with G4LDB are listed at g4ldb.org/ci2/index.php/other/ compatibility. [8] The ligands or the bioactive compounds taken from the literature studies are drawn using Accelrys Draw. These compounds are converted to 3D structures and using online SMILES translator; these 3D structures are converted to SMILES format. These SMILES formats for the respective compounds are pasted in the Compute Docking module and docked with the respective proteins, and these proteins are selected based on the literature survey. The proteins Table 2: Lipinski s rule Molecular weight Log p Hydrogen bond acceptor Hydrogen bond donor Resveratrol Gallic acid Quercetin Stigmasterol Piceatonnol Asarone Luteolin Table 3: G quadruplex targets of plant chemical constituents with their dock score values Ligands (pki) 1L1H 10OK 2HRI 3CE5 3NYP 3SC8 Resveratrol Gallic acid Quercetin Stigmasterol Piceatonnol Asarone Luteolin

3 selected for the study are 1L1H, 10OK, 2HRI, 3CE5, 3NYP, and 3SC8. The binding free energy was obtained for each ligand, and the contact analysis of the docked complexes was done using Discovery Studio 4.1 Visualizer. The visualization can also be viewed by Java which was installed in the G4LDB database. The dock score values are tabulated in Table 3. From the results, best dock score of the particular ligands are selected, and these are tabulated in Table 4. Discovery Studio 4.1 Visualizer is a free, molecular modeling environment, for both small molecule and macromolecule applications. It is developed by Accelrys which specializes in scientific software products. It is used regularly in a range of academic and commercial entities but is most relevant to pharmaceutical and biotechnology industries. The visualization of the docked compounds is tabulated in Table 5a and b. RESULTS AND DISCUSSION The pharmacological activities of the medicinal plant, CQ, are antioxidant, anti-inflammatory, antiulcer, bone healing, analgesic, and diuretic. In this study, we focused on the anticancer activity of the plant. [9] The plant compounds better binding features with the targets. The bioactive compounds such as resveratrol, gallic acid, quercetin, piceatannol, asarone, and Table 4: Final dock score of the selected compounds Ligands (pki) 1L1H 3NYP 10OK 3CE5 Resveratrol Gallic acid Quercetin Stigmasterol Piceatannol Asarone Luteolin luteolin showed good binding energy. Thus, these compounds can be effectively used as drugs for treating the anticancer activity. The insights gained in this work can be further used in experimental studies to develop drug leads which are more potent and less toxic. CONCLUSION In the recent cancer studies, most of the synthetic drugs produce undesirable side effects. Various studies showed that plant source produces potent and safer anti-cancer drugs. Hence, in this present study, plant source was selected. CQ has been used helminthiasis, anorexia, dyspepsia, flatulence, skin diseases, leprosy, epilepsy convulsions, and rheumatoid arthritis and has a rich amount of flavonoids. The medical treatment of cancer has made substantial improvements since the early years of modern antitumor drug research. Selected number malignancies can be cured with the today s therapies, and prolonged survival has been obtained in several others. The identification and development of natural compounds and their derivatives have greatly contributed to this progress, and many of these compounds are now being used in clinical practice. Flavonoids have a capacity to elevate the antioxidant levels and prevent the free radical reactions. Hence, the present in silico study CQ has a high amount of flavonoid and phenolic content, and these can be taken as a tool to design new compounds and to synthesize the compounds very efficiently. ACKNOWLEDGMENT The authors are very thankful to Vels Institute of Science Technology and Advanced Studies (VISTAS) and its management for providing research facilities and encouragement. Table 5a: Visualization of the docked compounds Stigmasterol Ligands 10OK 3CE5 766

4 Table 5b: Visualization of the docked compounds Resveratrol Ligands 1L1H 3NYP Gallic acid Quercetin Piceatannol Asarone Luteolin 767

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