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Prediction of new cyanobacterial drug for treating lung cancer
Biomedicine & Aging Pathology 4 (2014) 49–52
Available online at
ScienceDirect www.sciencedirect.com
Original article
Prediction of new cyanobacterial drug for treating lung cancer Subramaniyan Vijayakumar ∗ , Muniaraj Menakha P.G. and Research Department of Botany and Microbiology, A.V.V.M. Sri Pushpam College (Autonomous), Poondi, Thanjavur district, Tamil Nadu, 613 503 India
a r t i c l e
i n f o
Article history: Received 17 October 2013 Accepted 14 November 2013 Available online 10 January 2014 Keywords: Lung cancer EGFR kinase Cyanobacterial drugs Tiglicamide A Lyngbya confervoides Glide Hex Insilico docking
a b s t r a c t Lung cancer causing EGFR kinase protein selected as target and treated against commercially available anticancer drugs and cyanobacterial compounds. The present study was to predict screen and identify the potential high efficient antilung cancer compounds from the marine flora of cyanobacteria. To screen the bioactive compounds against lung cancer causing protein, EGFR kinase, Glide module (Schrodinger suite) was applied. Among the 33 bioactive compounds screened, best Glide docking score of −10.485 was found in Tiglicamide A against EGFR kinase. When this Tiglicamide A was compared with the commercially available drugs like cabazitaxel and apraclonidine through molecular docking, Tiglicamide A was found to be more effective by interacting strongly with lung cancer causing target protein, EGFR kinase. The results of the study support the fact that in silico molecular docking studies using Glide and Hex programs are very useful in predicting lung cancer treating drug. In this study, Tiglicamide A was predicted as the best active cyanobacterial compound derived from Lyngbya confervoides. Crown Copyright © 2013 Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Lung cancer is an uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung and other parts of the body. Most cancers that start in lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. The main types of lung cancer are small cell lung carcinoma and non-small cell lung carcinoma. The most common cause of lung cancer is long-term exposure to tobacco smoke. The lung cancer is often attributed to a combination of genetic factors, radon gas, and asbestos and air pollution including second-hand smoke [1]. Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes. Oncogenes are believed to make people more susceptible to cancer. The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion. Mutations and amplification of EGFR are common in non-small cell lung cancer [2]. Common treatments include surgery, chemotherapy, and radiotherapy. The chemotherapy regimen depends on the tumor type [3]. Small cell lung carcinoma (SCLC), even relatively early stage disease, is treated primarily with chemotherapy and radiation. In SCLC, cisplatin and etoposide are most commonly used. Combinations
∗ Corresponding author. Tel.: +91 04374 239523; fax: +91 04374 239477. E-mail address: svijaya [email protected] (S. Vijayakumar).
with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan are also used. In advanced non-small cell lung carcinoma (NSCLC), chemotherapy improves survival and is used as first-line treatment, provided the person is well enough for the treatment. Typically, two drugs are used, of which one is often platinum-based (either cisplatin or carboplatin). Other commonly used drugs are gemcitabine, paclitaxel, docetaxel, pemetrexed, etoposide or vinorelbine [4]. Cancer treatments do not have potent medicine as the currently available drugs are causing side effects in some instances. At present commonly used antitumor drugs are cabazitaxel and apraclonidine in which side effects are so common. Therefore, drug identification from natural resource for the prevention and treatment of cancer is continuing in the last three decades. Numerous types of bioactive compounds have been isolated from marine cyanobacteria. Several of them are currently in clinical trials or preclinical trials or undergoing further investigation. However, developments of marine floral compounds as therapeutic agents are still in the developing stage [5]. Studies have clearly demonstrated that the cyanobacteria are an excellent source of novel drug discovery. Marine cyanobacteria are considered to be a group of potential organisms which can be the richest sources of known and novel bioactive compounds [6,7]. More than 50% of the marine cyanobacteria are potentially exploitable for extracting bioactive substances which are effective in either killing the cancer cells by inducing apoptotic death. Identification of new biologically active compounds is required for development of new drugs. Nowadays, molecular docking
2210-5220/$ – see front matter. Crown Copyright © 2013 Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.biomag.2013.11.002
50
S. Vijayakumar, M. Menakha / Biomedicine & Aging Pathology 4 (2014) 49–52 Table 1 Docking results of EGFR kinase with cyanobacterial compounds using Glide docking.
Fig. 1. 3D structure of EGFR kinase.
approaches are routinely used in modern drug design to understand drug-receptor interaction. It has been shown in the literature that these computational techniques can strongly support and help the design of novel, more potent inhibitors by revealing the mechanism of drug-receptor interaction [8]. Hence, the present study has planned to evaluate the interaction of the anticancer drugs administered for the target of lung cancer. At present, commonly used antitumor drugs are cabazitaxel and apraclonidine in which side effects are so common. In lung cancer, EGFR kinase is to be controlled by effective antitumor compounds. Therefore, in the present investigation, suitable drug molecules with high binding affinity, which could be a possible lead molecule derived from cyanobacterial compounds are to be proposed. 2. Material and methods The lung cancer causing receptor was retrieved from Protein database. [9]. The commercially available drug, apraclonidine and cabazitaxel and cyanobacterial drugs were retrieved from Chemspider database [10], which were later converted into 3D structures using Swiss Pdb viewer [11]. Thirty-three cyanobacterial compounds were screened for the identification of better bioactive compound using Glide module (Schrodinger suite). The potential identified cyanobacterial drug, Tiglicamide A and commercially available drug molecules were docked with the receptor molecule EGFR kinase using Hex software [12]. 3. Results and discussion Lung cancer is caused by EGFR kinase [13]. At present, commonly used antilung cancer drugs are cabazitaxel and apraclonidine in which side effects are so common [14]. EGFR kinase is a protein molecule containing a single chain formed by 327 amino acids (Fig. 1). In lung cancer, EGFR kinase is to be controlled by effective antitumor compounds. Therefore, in the present investigation, suitable drug molecules with high binding affinity, which could be a possible lead molecule derived from cyanobacterial compounds are to be proposed. 4. Drug molecules Currently, for cancer treatment, adequate potent medicines are not available. Marine cyanobacteria are considered to be the
Cyanobacterial drugs
Source organisms
Antillatoxin 2 Apratoxin B1 Arulide 3 Baslynbiyaside Belamide A2 Basibroamide 1 Calothrixin B Caylobolide A2 Cryptophycin 226 Kemopeptinde B Hoamide C Homodolastin 16 Isomalgamide B Lagunamide C Lynbyabelin C Lynbaysolide B1 Lyngbastatin 6 Majusculamide D Maleviamide D Malyngamide R Malyngolide 1 Nostocylopeptide Obynanaide 2 Pitipeptolide D Pitiprolamide Pompanopeptin Somocystinamide A Symplocamide A Symplostatin 2 Tasipeptin B Tasiamide B Tiglicamide A VeraguamideF
Lyngbya majuscula Lyngbya sp. Lyngbya majuscule Lyngbya sp. Symploca sp. Lyngbya sp. Calothrix Lyngbya majuscula Nostoc sp. Lyngbya sp. Phormidium gracile Lyngbya majuscula Lyngbya majuscula Lyngbya majuscula Lyngbya majuscule Lyngbya sp. Lyngbya majuscule Lyngbya majuscule Symploca hydnoides Lyngbya majuscula Lyngbya sordida Nostoc sp. Lyngbya confervoides Lyngbya majuscule Lyngbya majuscule Lyngbya confervoides Lyngbya majuscule Symploca sp. Symploca hydnoides Symploca sp. Symploca sp. Lyngbya confervoides Symploca hydnoides
Glide docking score −4.902 −6.988 −5.718 −6.235 −6.542 −7.829 −7.485 −8.410 −7.962 −9.458 −6.003 −8.171 −5.634 −6.104 −8.102 −6.639 −9.065 −7.332 −6.664 −6.157 −3.866 −9.230 −5.277 −6.184 −3.866 −8.949 −4.653 −9.879 −9.151 −6.981 −8.239 −10.485 −7.527
Selected drug represented in bold.
potential organisms as rich source of known and novel bioactive compounds, which are effective in either killing the cancer cells or affecting the cell signaling for cancer [15]. Among the various members of marine cyanobacteria, Calothrix, Lyngbya sp., Lyngbya confervoides, Lyngbya majuscule, Lyngbya sordida, Nostoc sp., Phormidium gracile, Symploca sp. and Symploca hydnoides are highly potential organisms having anticancer drug molecules such as Antillatoxin 2, Apratoxin B1, Arulide 3, Baslynbiyaside, Belamide A2, Basibroamide 1, Calothrixin B, Caylobolide A2, Cryptophycin 226, Kemopeptinde B, Hoamide C, Homodolastin 16, Isomalgamide B, Lagunamide C, Lynbyabelin C, Lynbaysolide B1, Lyngbastatin 6, Majusculamide D, Maleviamide D, Malyngamide R, Malyngolide 1, Nostocylopeptide, Obynanaide 2, Pitipeptolide D, Pitiprolamide, Pompanopeptin, Somocystinamide A, Symplocamide A, Symplostatin 2, Tasipeptin B, Tasiamide B, Tiglicamide A and Veraguamide F. When these drug molecules were docked with the lung cancer causing receptor molecule EGFR kinase, Tiglicamide A showed a maximum Glide score indicating effective molecules against receptor tumor causing molecule (Table 1). From this result, it is concluded that among the various cyanobacterial anticancer compounds, Tiglicamide A was identified as the best antilung cancer molecule (Table 2). Currently, cabazitaxel (Fig. 2) and apraclonidine (Fig. 3) are used as anticancer drugs for lung cancer. In the present study, TiglicamideA (Fig. 4) has been identified as anticancer drug for lung Table 2 Docking results of EGFR kinase with anticancer drugs. Lung cancer causing protein
Anticancer drugs
Docking score (e-value)
EGFR kinase
Cabazitaxel Apraclonidine Tiglicamide A
−332.35 −175.91 −434.01
S. Vijayakumar, M. Menakha / Biomedicine & Aging Pathology 4 (2014) 49–52
51
Fig. 2. 3D structure of cabazitaxel. Fig. 5. Molecular docking of EGFR kinase with Tiglicamide A.
Fig. 3. 3D structure of apraclonidine.
cancer, in addition to the above two drugs. In order to find out which of the three drugs is more effective for the lung cancer treatment, molecular docking was carried out using Hex software. Docking results between lung cancer causing receptor and the conventional drugs (cabazitaxel and apraclonidine) and the cyanobacterial drug Tiglicamide A were tabulated. These drugs have been used to target the lung cancer causing receptor. These drug molecules bound
to the receptor and inhibit its function. The nature of the complex between the drug and the receptor complex was identified via docking and their relative stabilities for inhibition were evaluated using molecular dynamics and their binding affinities using free energy simulations. In this study, Tiglicamide A showed a maximum e-value −434.01 against lung cancer causing molecule followed by cabazitaxel having the e-value of −332.35. The third molecule apraclonidine showed the least value of −175.91 (Table 2). When comparing the commercially available drugs currently used for the treatment, Tiglicamide A, a compound of cyanobacterial origin is considered to be better and more effective in treating the lung cancer causing receptor molecule. The Tiglicamide A molecule showed a high binding affinity with the major active site of lung cancer causing receptor molecule (Fig. 5). 5. Conclusions The above study concluded that 33 cyanobacterial compounds from 9 species were docked against lung cancer causing receptor molecule, out of which Tiglicamide A from Lyngbya confervoides was selected and showed a strong interaction and binding with target proteins evidenced by having best docking score with the help of Glide module (Schrodinger suite) when compared to other tested ligands. Based on the results of the present study it can be concluded that the drug Tiglicamide A is the very effective anticancer drug against lung cancer. The effectiveness of Tiglicamide A was compared with the commercially available drugs like cabazitaxel and apraclonidine using Hex software. Among the three, Tiglicamide A was found to be the most effective drug against lung cancer. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgement
Fig. 4. 3D structure of Tiglicamide A.
The authors are grateful to the UGC Major Research project, New Delhi, India (MRP R. No: 41-472/2012 (SR)) for providing fund for this project. We specially express our thanks to the management of A.V.V.M. Sri Pushpam College (Autonomous), Poondi, for providing the necessary facilities and support to carry out this work.
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S. Vijayakumar, M. Menakha / Biomedicine & Aging Pathology 4 (2014) 49–52
References [1] Horn L, Pao W, Johnson DH. Harrison’s principles of internal medicine. Chapter 89. 18th ed McGraw-Hill; 2012. ISBN: 0-07-174889-X. [2] Salgia R, Skarin AT. Molecular abnormalities in lung cancer. J Clin Oncol 1998;16(3):1207–17 [PMID 9508209]. [3] Lu C, Onn A, Vaporciyan AA. Cancer of the Lung. Holland-Frei Cancer Medicine. 8th ed People’s Medical Publishing House; 2010. ISBN: 9781607950141. [4] Clegg A, Scott DA, Hewitson P. Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 2002;57(1):20–8 [PMID 11809985]. [5] Jimeno J, Faircloth G, Fernández Sousa-Faro JM, Scheuer P, Rinehart K. New marine derived anticancer therapeutics—a journey from the sea to clinical trials. Mar Drugs 2004;2:14–29. [6] Jha RK, Zi-Rong X. Biomedical compounds from marine organisms. Mar Drugs 2004;2:123–46.
[7] Thajuddin N, Subramanian G. Cyanobacterial biodiversity and potential applications in biotechnology. Curr Sci 2005;89(1):47–57. [8] Xie L, Wang J, Bourne PE. In silico elucidation of the molecular mechanism defining the adverse effect of selective estrogen receptor modulators. PLoS Comput Biol 2007;3:e217. [9] www.rcsb.org [10] www.chemspider.com/ [11] www.genebee.msu.su/sp [12] www.hex.loria.fr/ [13] Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497–500 [PMID 15118125]. [14] Gaikwad A, Harish Sura B, Shaphrang K, Moutrisha Ray S, Krishnan K. Prediction of interaction between antitumor compounds and target proteins of different cancers by in silico molecular docking studies. Pharmacol Online 2011;3:692–9. [15] Gurib-Fakim A. Medicinal plants: traditions of yesterday and drugs of tomorrow. Mol Aspects Med 2006;27(1):1–93.
Available online at
ScienceDirect www.sciencedirect.com
Original article
Prediction of new cyanobacterial drug for treating lung cancer Subramaniyan Vijayakumar ∗ , Muniaraj Menakha P.G. and Research Department of Botany and Microbiology, A.V.V.M. Sri Pushpam College (Autonomous), Poondi, Thanjavur district, Tamil Nadu, 613 503 India
a r t i c l e
i n f o
Article history: Received 17 October 2013 Accepted 14 November 2013 Available online 10 January 2014 Keywords: Lung cancer EGFR kinase Cyanobacterial drugs Tiglicamide A Lyngbya confervoides Glide Hex Insilico docking
a b s t r a c t Lung cancer causing EGFR kinase protein selected as target and treated against commercially available anticancer drugs and cyanobacterial compounds. The present study was to predict screen and identify the potential high efficient antilung cancer compounds from the marine flora of cyanobacteria. To screen the bioactive compounds against lung cancer causing protein, EGFR kinase, Glide module (Schrodinger suite) was applied. Among the 33 bioactive compounds screened, best Glide docking score of −10.485 was found in Tiglicamide A against EGFR kinase. When this Tiglicamide A was compared with the commercially available drugs like cabazitaxel and apraclonidine through molecular docking, Tiglicamide A was found to be more effective by interacting strongly with lung cancer causing target protein, EGFR kinase. The results of the study support the fact that in silico molecular docking studies using Glide and Hex programs are very useful in predicting lung cancer treating drug. In this study, Tiglicamide A was predicted as the best active cyanobacterial compound derived from Lyngbya confervoides. Crown Copyright © 2013 Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Lung cancer is an uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung and other parts of the body. Most cancers that start in lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. The main types of lung cancer are small cell lung carcinoma and non-small cell lung carcinoma. The most common cause of lung cancer is long-term exposure to tobacco smoke. The lung cancer is often attributed to a combination of genetic factors, radon gas, and asbestos and air pollution including second-hand smoke [1]. Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes. Oncogenes are believed to make people more susceptible to cancer. The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion. Mutations and amplification of EGFR are common in non-small cell lung cancer [2]. Common treatments include surgery, chemotherapy, and radiotherapy. The chemotherapy regimen depends on the tumor type [3]. Small cell lung carcinoma (SCLC), even relatively early stage disease, is treated primarily with chemotherapy and radiation. In SCLC, cisplatin and etoposide are most commonly used. Combinations
∗ Corresponding author. Tel.: +91 04374 239523; fax: +91 04374 239477. E-mail address: svijaya [email protected] (S. Vijayakumar).
with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan are also used. In advanced non-small cell lung carcinoma (NSCLC), chemotherapy improves survival and is used as first-line treatment, provided the person is well enough for the treatment. Typically, two drugs are used, of which one is often platinum-based (either cisplatin or carboplatin). Other commonly used drugs are gemcitabine, paclitaxel, docetaxel, pemetrexed, etoposide or vinorelbine [4]. Cancer treatments do not have potent medicine as the currently available drugs are causing side effects in some instances. At present commonly used antitumor drugs are cabazitaxel and apraclonidine in which side effects are so common. Therefore, drug identification from natural resource for the prevention and treatment of cancer is continuing in the last three decades. Numerous types of bioactive compounds have been isolated from marine cyanobacteria. Several of them are currently in clinical trials or preclinical trials or undergoing further investigation. However, developments of marine floral compounds as therapeutic agents are still in the developing stage [5]. Studies have clearly demonstrated that the cyanobacteria are an excellent source of novel drug discovery. Marine cyanobacteria are considered to be a group of potential organisms which can be the richest sources of known and novel bioactive compounds [6,7]. More than 50% of the marine cyanobacteria are potentially exploitable for extracting bioactive substances which are effective in either killing the cancer cells by inducing apoptotic death. Identification of new biologically active compounds is required for development of new drugs. Nowadays, molecular docking
2210-5220/$ – see front matter. Crown Copyright © 2013 Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.biomag.2013.11.002
50
S. Vijayakumar, M. Menakha / Biomedicine & Aging Pathology 4 (2014) 49–52 Table 1 Docking results of EGFR kinase with cyanobacterial compounds using Glide docking.
Fig. 1. 3D structure of EGFR kinase.
approaches are routinely used in modern drug design to understand drug-receptor interaction. It has been shown in the literature that these computational techniques can strongly support and help the design of novel, more potent inhibitors by revealing the mechanism of drug-receptor interaction [8]. Hence, the present study has planned to evaluate the interaction of the anticancer drugs administered for the target of lung cancer. At present, commonly used antitumor drugs are cabazitaxel and apraclonidine in which side effects are so common. In lung cancer, EGFR kinase is to be controlled by effective antitumor compounds. Therefore, in the present investigation, suitable drug molecules with high binding affinity, which could be a possible lead molecule derived from cyanobacterial compounds are to be proposed. 2. Material and methods The lung cancer causing receptor was retrieved from Protein database. [9]. The commercially available drug, apraclonidine and cabazitaxel and cyanobacterial drugs were retrieved from Chemspider database [10], which were later converted into 3D structures using Swiss Pdb viewer [11]. Thirty-three cyanobacterial compounds were screened for the identification of better bioactive compound using Glide module (Schrodinger suite). The potential identified cyanobacterial drug, Tiglicamide A and commercially available drug molecules were docked with the receptor molecule EGFR kinase using Hex software [12]. 3. Results and discussion Lung cancer is caused by EGFR kinase [13]. At present, commonly used antilung cancer drugs are cabazitaxel and apraclonidine in which side effects are so common [14]. EGFR kinase is a protein molecule containing a single chain formed by 327 amino acids (Fig. 1). In lung cancer, EGFR kinase is to be controlled by effective antitumor compounds. Therefore, in the present investigation, suitable drug molecules with high binding affinity, which could be a possible lead molecule derived from cyanobacterial compounds are to be proposed. 4. Drug molecules Currently, for cancer treatment, adequate potent medicines are not available. Marine cyanobacteria are considered to be the
Cyanobacterial drugs
Source organisms
Antillatoxin 2 Apratoxin B1 Arulide 3 Baslynbiyaside Belamide A2 Basibroamide 1 Calothrixin B Caylobolide A2 Cryptophycin 226 Kemopeptinde B Hoamide C Homodolastin 16 Isomalgamide B Lagunamide C Lynbyabelin C Lynbaysolide B1 Lyngbastatin 6 Majusculamide D Maleviamide D Malyngamide R Malyngolide 1 Nostocylopeptide Obynanaide 2 Pitipeptolide D Pitiprolamide Pompanopeptin Somocystinamide A Symplocamide A Symplostatin 2 Tasipeptin B Tasiamide B Tiglicamide A VeraguamideF
Lyngbya majuscula Lyngbya sp. Lyngbya majuscule Lyngbya sp. Symploca sp. Lyngbya sp. Calothrix Lyngbya majuscula Nostoc sp. Lyngbya sp. Phormidium gracile Lyngbya majuscula Lyngbya majuscula Lyngbya majuscula Lyngbya majuscule Lyngbya sp. Lyngbya majuscule Lyngbya majuscule Symploca hydnoides Lyngbya majuscula Lyngbya sordida Nostoc sp. Lyngbya confervoides Lyngbya majuscule Lyngbya majuscule Lyngbya confervoides Lyngbya majuscule Symploca sp. Symploca hydnoides Symploca sp. Symploca sp. Lyngbya confervoides Symploca hydnoides
Glide docking score −4.902 −6.988 −5.718 −6.235 −6.542 −7.829 −7.485 −8.410 −7.962 −9.458 −6.003 −8.171 −5.634 −6.104 −8.102 −6.639 −9.065 −7.332 −6.664 −6.157 −3.866 −9.230 −5.277 −6.184 −3.866 −8.949 −4.653 −9.879 −9.151 −6.981 −8.239 −10.485 −7.527
Selected drug represented in bold.
potential organisms as rich source of known and novel bioactive compounds, which are effective in either killing the cancer cells or affecting the cell signaling for cancer [15]. Among the various members of marine cyanobacteria, Calothrix, Lyngbya sp., Lyngbya confervoides, Lyngbya majuscule, Lyngbya sordida, Nostoc sp., Phormidium gracile, Symploca sp. and Symploca hydnoides are highly potential organisms having anticancer drug molecules such as Antillatoxin 2, Apratoxin B1, Arulide 3, Baslynbiyaside, Belamide A2, Basibroamide 1, Calothrixin B, Caylobolide A2, Cryptophycin 226, Kemopeptinde B, Hoamide C, Homodolastin 16, Isomalgamide B, Lagunamide C, Lynbyabelin C, Lynbaysolide B1, Lyngbastatin 6, Majusculamide D, Maleviamide D, Malyngamide R, Malyngolide 1, Nostocylopeptide, Obynanaide 2, Pitipeptolide D, Pitiprolamide, Pompanopeptin, Somocystinamide A, Symplocamide A, Symplostatin 2, Tasipeptin B, Tasiamide B, Tiglicamide A and Veraguamide F. When these drug molecules were docked with the lung cancer causing receptor molecule EGFR kinase, Tiglicamide A showed a maximum Glide score indicating effective molecules against receptor tumor causing molecule (Table 1). From this result, it is concluded that among the various cyanobacterial anticancer compounds, Tiglicamide A was identified as the best antilung cancer molecule (Table 2). Currently, cabazitaxel (Fig. 2) and apraclonidine (Fig. 3) are used as anticancer drugs for lung cancer. In the present study, TiglicamideA (Fig. 4) has been identified as anticancer drug for lung Table 2 Docking results of EGFR kinase with anticancer drugs. Lung cancer causing protein
Anticancer drugs
Docking score (e-value)
EGFR kinase
Cabazitaxel Apraclonidine Tiglicamide A
−332.35 −175.91 −434.01
S. Vijayakumar, M. Menakha / Biomedicine & Aging Pathology 4 (2014) 49–52
51
Fig. 2. 3D structure of cabazitaxel. Fig. 5. Molecular docking of EGFR kinase with Tiglicamide A.
Fig. 3. 3D structure of apraclonidine.
cancer, in addition to the above two drugs. In order to find out which of the three drugs is more effective for the lung cancer treatment, molecular docking was carried out using Hex software. Docking results between lung cancer causing receptor and the conventional drugs (cabazitaxel and apraclonidine) and the cyanobacterial drug Tiglicamide A were tabulated. These drugs have been used to target the lung cancer causing receptor. These drug molecules bound
to the receptor and inhibit its function. The nature of the complex between the drug and the receptor complex was identified via docking and their relative stabilities for inhibition were evaluated using molecular dynamics and their binding affinities using free energy simulations. In this study, Tiglicamide A showed a maximum e-value −434.01 against lung cancer causing molecule followed by cabazitaxel having the e-value of −332.35. The third molecule apraclonidine showed the least value of −175.91 (Table 2). When comparing the commercially available drugs currently used for the treatment, Tiglicamide A, a compound of cyanobacterial origin is considered to be better and more effective in treating the lung cancer causing receptor molecule. The Tiglicamide A molecule showed a high binding affinity with the major active site of lung cancer causing receptor molecule (Fig. 5). 5. Conclusions The above study concluded that 33 cyanobacterial compounds from 9 species were docked against lung cancer causing receptor molecule, out of which Tiglicamide A from Lyngbya confervoides was selected and showed a strong interaction and binding with target proteins evidenced by having best docking score with the help of Glide module (Schrodinger suite) when compared to other tested ligands. Based on the results of the present study it can be concluded that the drug Tiglicamide A is the very effective anticancer drug against lung cancer. The effectiveness of Tiglicamide A was compared with the commercially available drugs like cabazitaxel and apraclonidine using Hex software. Among the three, Tiglicamide A was found to be the most effective drug against lung cancer. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgement
Fig. 4. 3D structure of Tiglicamide A.
The authors are grateful to the UGC Major Research project, New Delhi, India (MRP R. No: 41-472/2012 (SR)) for providing fund for this project. We specially express our thanks to the management of A.V.V.M. Sri Pushpam College (Autonomous), Poondi, for providing the necessary facilities and support to carry out this work.
52
S. Vijayakumar, M. Menakha / Biomedicine & Aging Pathology 4 (2014) 49–52
References [1] Horn L, Pao W, Johnson DH. Harrison’s principles of internal medicine. Chapter 89. 18th ed McGraw-Hill; 2012. ISBN: 0-07-174889-X. [2] Salgia R, Skarin AT. Molecular abnormalities in lung cancer. J Clin Oncol 1998;16(3):1207–17 [PMID 9508209]. [3] Lu C, Onn A, Vaporciyan AA. Cancer of the Lung. Holland-Frei Cancer Medicine. 8th ed People’s Medical Publishing House; 2010. ISBN: 9781607950141. [4] Clegg A, Scott DA, Hewitson P. Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review. Thorax 2002;57(1):20–8 [PMID 11809985]. [5] Jimeno J, Faircloth G, Fernández Sousa-Faro JM, Scheuer P, Rinehart K. New marine derived anticancer therapeutics—a journey from the sea to clinical trials. Mar Drugs 2004;2:14–29. [6] Jha RK, Zi-Rong X. Biomedical compounds from marine organisms. Mar Drugs 2004;2:123–46.
[7] Thajuddin N, Subramanian G. Cyanobacterial biodiversity and potential applications in biotechnology. Curr Sci 2005;89(1):47–57. [8] Xie L, Wang J, Bourne PE. In silico elucidation of the molecular mechanism defining the adverse effect of selective estrogen receptor modulators. PLoS Comput Biol 2007;3:e217. [9] www.rcsb.org [10] www.chemspider.com/ [11] www.genebee.msu.su/sp [12] www.hex.loria.fr/ [13] Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497–500 [PMID 15118125]. [14] Gaikwad A, Harish Sura B, Shaphrang K, Moutrisha Ray S, Krishnan K. Prediction of interaction between antitumor compounds and target proteins of different cancers by in silico molecular docking studies. Pharmacol Online 2011;3:692–9. [15] Gurib-Fakim A. Medicinal plants: traditions of yesterday and drugs of tomorrow. Mol Aspects Med 2006;27(1):1–93.