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��ࡱ�>��	UX����RST�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������[�	��0P�bjbj����;ΐΐ�E
���������     ����4448ld��4�RTlV�!�!�!�!�%�%�%�Q�Q�Q�Q�Q�Q�Q$U��W��Q� �%�%�%�%�%�Q  �!�!�~R�(�(�(�%� �! �!�Q�(�%�Q�(�(�*+�!������zBv�4W&^�*�Q�R0�R�*,�X�&��X++��X �3��%�%�(�%�%�%�%�%�Q�Q�(�%�%�%�R�%�%�%�%���������������������������������������������������������������������X�%�%�%�%�%�%�%�%�%��:In silico inhibition studies of AXL kinase by curcumin and its natural derivatives 
Ghrifi. Fatima*, Allam. Loubna,  Lakhlili.Wiame and Ibrahimi Azeddine  
The Biotechnology Lab (MedBiotech), Rabat Medical and Pharmacy School, Mohammed V University in Rabat, Morocco 
*Corresponding Author
Biotechnology Lab (MedBiotech), Rabat Medical and Pharmacy School, Mohammed V University in Rabat, Avenue Mes belarbi Alaoui, Suissi-Rabat, BP6203 Rabat instituts,Rabat,10000, Morocco 
Tel+212�537 77 28 50
Fax +212 53�777 37 01
e-mail: ghrifatima1000@gmail.com












Abstract     
The last few years have seen the intensive investigation efforts for understanding the wide relevance of AXL activation in multiple aspects of oncogenesis, invasion, metastasis and drug resistance. Therfore, targeting AXL can be considered as one of the promissing approaches for the treatement of cancer. A series of curcumin derivatives which are natural polyphenolic coumponds were well-reported as an anti cancer and chemopreventive agents. We have investigated them as an ATP-competitive inhibitors of AXL kinase by using a docking studies. We built a model of AXL catalytic domain from the crystal structure of proto-oncogene tyrosine-protein kinase MER (MERTK) and the modeling of the three-dimensional (3D) structure of the AXL was performed by SWISS-MODEL homology modeling program.The quality and validation of the model were performed using PROCHECK and VERIFY 3D softwares. The Ramachandran plot was used to validate the overall stereochemical property of the protein. All curcuminoids formed a hydrogen bond with hinge region by Methionine (Met 623) and lysine (Lys 567) indicating that these compounds can be utilized therapeutically as a natural AXL inhibitors.
Keywords:  AXL Kinase, Curcumin, Docking, Homology modeling.









Introduction
The AXL receptor tyrosine kinase , also known as UFO, Tyro7 and Ark, is a member of the tyrosine kinases receptors family TAM (Tyro3, AXL and MERTK)  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cizZHWEL","properties":{"formattedCitation":"(1)","plainCitation":"(1)"},"citationItems":[{"id":288,"uris":["http://zotero.org/users/local/i8pMETai/items/JQMSKKDN"],"uri":["http://zotero.org/users/local/i8pMETai/items/JQMSKKDN"],"itemData":{"id":288,"type":"article-journal","title":"Biology of the TAM receptors","container-title":"Cold Spring Harbor Perspectives in Biology","page":"a009076","volume":"5","issue":"11","source":"PubMed","abstract":"The TAM receptors--Tyro3, Axl, and Mer--comprise a unique family of receptor tyrosine kinases, in that as a group they play no essential role in embryonic development. Instead, they function as homeostatic regulators in adult tissues and organ systems that are subject to continuous challenge and renewal throughout life. Their regulatory roles are prominent in the mature immune, reproductive, hematopoietic, vascular, and nervous systems. The TAMs and their ligands--Gas6 and Protein S--are essential for the efficient phagocytosis of apoptotic cells and membranes in these tissues; and in the immune system, they act as pleiotropic inhibitors of the innate inflammatory response to pathogens. Deficiencies in TAM signaling are thought to contribute to chronic inflammatory and autoimmune disease in humans, and aberrantly elevated TAM signaling is strongly associated with cancer progression, metastasis, and resistance to targeted therapies.","DOI":"10.1101/cshperspect.a009076","ISSN":"1943-0264","note":"PMID: 24186067\nPMCID: PMC3809585","journalAbbreviation":"Cold Spring Harb Perspect Biol","language":"eng","author":[{"family":"Lemke","given":"Greg"}],"issued":{"date-parts":[["2013",11,1]]},"PMID":"24186067","PMCID":"PMC3809585"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (1). AXL, like the other TAM members, its activated  via the interaction with the growth arrest-specific protein 6 (GAS6) ligand  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PUFPd06O","properties":{"formattedCitation":"(2)","plainCitation":"(2)"},"citationItems":[{"id":257,"uris":["http://zotero.org/users/local/i8pMETai/items/9PUE45ZQ"],"uri":["http://zotero.org/users/local/i8pMETai/items/9PUE45ZQ"],"itemData":{"id":257,"type":"article-journal","title":"Characterization of Gas6, a member of the superfamily of G domain-containing proteins, as a ligand for Rse and Axl","container-title":"The Journal of Biological Chemistry","page":"9785-9789","volume":"271","issue":"16","source":"PubMed","abstract":"Rse, Ax1, and c-Mer comprise a family of cell adhesion molecule-related tyrosine kinase receptors. Human Gas6 was recently shown to act as a ligand for both human Rse (Godowski et al., 1995) and human Ax1 (Varnum et al., 1995). Gas6 contains an NH2-terminal Gla domain followed by four epidermal growth factor-like repeats and tandem globular (G) domains. The G domains are related to those found in sex hormone-binding globulin and to those utilized by laminin and agrin for binding to the dystroglycan complex. A series of Gas6 variants were tested for their ability to bind to Rse and Ax1. The Gla domain and epidermal growth factor-like repeats were not required for receptor binding, as deletion variants of Gas6 which lacked these domains bound to the extracellular domains of both Rse and Axl. A deletion variant of Gas6 containing just the G domain region was shown to activate Rse phosphorylation. These results provide evidence that G domains can act as signaling molecules by activating transmembrane receptor tyrosine kinases. Furthermore, they provide a structural link between the activation of cell adhesion related receptors and the control of cell growth and differentiation by the G domain-containing superfamily of proteins.","ISSN":"0021-9258","note":"PMID: 8621659","journalAbbreviation":"J. Biol. Chem.","language":"eng","author":[{"family":"Mark","given":"M. R."},{"family":"Chen","given":"J."},{"family":"Hammonds","given":"R. G."},{"family":"Sadick","given":"M."},{"family":"Godowsk","given":"P. J."}],"issued":{"date-parts":[["1996",4,19]]},"PMID":"8621659"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (2). The receptor has been implicated in a number of oncogenic processes. AXL signalization enhances many essential biological functions for cancer formation and progression, including invasion, migration, survival, angiogenesis, cell transformation and proliferation   ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FZNaZQlo","properties":{"formattedCitation":"(3)","plainCitation":"(3)"},"citationItems":[{"id":131,"uris":["http://zotero.org/users/local/i8pMETai/items/PM7TNVGT"],"uri":["http://zotero.org/users/local/i8pMETai/items/PM7TNVGT"],"itemData":{"id":131,"type":"article-journal","title":"TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer","container-title":"Advances in Cancer Research","page":"35-83","volume":"100","source":"PubMed","abstract":"Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and downstream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are overexpressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer.","DOI":"10.1016/S0065-230X(08)00002-X","ISSN":"0065-230X","note":"PMID: 18620092\nPMCID: PMC3133732","shortTitle":"TAM receptor tyrosine kinases","journalAbbreviation":"Adv. Cancer Res.","language":"eng","author":[{"family":"Linger","given":"Rachel M. A."},{"family":"Keating","given":"Amy K."},{"family":"Earp","given":"H. Shelton"},{"family":"Graham","given":"Douglas K."}],"issued":{"date-parts":[["2008"]]},"PMID":"18620092","PMCID":"PMC3133732"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (3). The increase of  AXL activity or overexpression indicates a poor prognosis for the patients and has been reported to be associated with  metastasis in several types of cancer  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"HGUmdUXZ","properties":{"formattedCitation":"(4)","plainCitation":"(4)"},"citationItems":[{"id":310,"uris":["http://zotero.org/users/local/i8pMETai/items/SGX2RSZX"],"uri":["http://zotero.org/users/local/i8pMETai/items/SGX2RSZX"],"itemData":{"id":310,"type":"article-journal","title":"Expression of axl in lung adenocarcinoma and correlation with tumor progression","container-title":"Neoplasia (New York, N.Y.)","page":"1058-1064","volume":"7","issue":"12","source":"PubMed","abstract":"We used the Transwell system to select highly invasive cell lines from minimally invasive parent cells, and we compared gene expression in paired cell lines with high and low invasive potentials. Axl was relatively overexpressed in the highly invasive cell lines when compared with their minimally invasive counterparts. However, there is only limited information about the role of Axl in cancer invasion. The biologic function of Axl in tumor invasion was investigated by overexpression of full-length Axl in minimally invasive cells and by siRNA knockdown of Axl expression in highly invasive cells. Overexpression of Axl in minimally invasive cells increased their invasiveness. siRNA reduced cell invasiveness as Axl was downregulated in highly invasive cells. We further investigated the protein expression of Axl by immunohistochemistry and its correlation with clinicopathologic features. Data from a study of 58 patient specimens showed that Axl immunoreactivity was statistically significant with respect to lymph node status (P < .0001) and the patient's clinical stage (P < .0001). Our results demonstrate that Axl protein kinase seems to play an important role in the invasion and progression of lung cancer.","ISSN":"1522-8002","note":"PMID: 16354588\nPMCID: PMC1501169","journalAbbreviation":"Neoplasia","language":"eng","author":[{"family":"Shieh","given":"Yi-Shing"},{"family":"Lai","given":"Chiung-Ya"},{"family":"Kao","given":"Yu-Rung"},{"family":"Shiah","given":"Shine-Gwo"},{"family":"Chu","given":"Yi-Wen"},{"family":"Lee","given":"Herng-Sheng"},{"family":"Wu","given":"Cheng-Wen"}],"issued":{"date-parts":[["2005",12]]},"PMID":"16354588","PMCID":"PMC1501169"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (4)  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FamoJsdO","properties":{"formattedCitation":"(5)","plainCitation":"(5)"},"citationItems":[{"id":308,"uris":["http://zotero.org/users/local/i8pMETai/items/MEWQ5KR8"],"uri":["http://zotero.org/users/local/i8pMETai/items/MEWQ5KR8"],"itemData":{"id":308,"type":"article-journal","title":"Clinical significance of AXL kinase family in gastric cancer","container-title":"Anticancer Research","page":"1071-1078","volume":"22","issue":"2B","source":"PubMed","abstract":"BACKGROUND: We have used degenerated PCR primers designed according to the consensus kinase motifs in order to amplify expressed protein tyrosine kinase molecules from human gastric cancers. From such kinase expression profiles, we have identified more than fifty different tyrosine and serine/threonine kinases from two matched pairs of gastric cancer tissue and normal mucosa. In previous studies, we have shown the clinical significance of two tyrosine kinases identified in gastric cancer, tie-1 and mkk4.\nMATERIALS AND METHODS: In this report, we further investigate the protein expression of the whole axl receptor tyrosine-kinase family (axl/ufo, nyk/mer and sky/rse) by immunohistochemistry and their clinicopathological associations.\nRESULTS: On examination of 96 patients specimens, expression of the axl kinase family alone showed no statistical significance with respect to the patients' survivaL However, the combination of nyk/mer expression with axl/ufo expression correlated inversely with the patients' prognosis result.\nCONCLUSION: This finding indicates that a co-operative relationship exists between axllufo and nyk/mer protein kinases and this seems to play an important role in gastric cancer progression and metastasis.","ISSN":"0250-7005","note":"PMID: 12168903","journalAbbreviation":"Anticancer Res.","language":"eng","author":[{"family":"Wu","given":"Chew-Wun"},{"family":"Li","given":"Anna F. Y."},{"family":"Chi","given":"Chin-Wen"},{"family":"Lai","given":"Chun-Hung"},{"family":"Huang","given":"Chen Lung"},{"family":"Lo","given":"Su-Shun"},{"family":"Lui","given":"Wing-Yiu"},{"family":"Lin","given":"Wen-Chang"}],"issued":{"date-parts":[["2002",4]]},"PMID":"12168903"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (5)  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"IMxnxEhD","properties":{"formattedCitation":"(6)","plainCitation":"(6)"},"citationItems":[{"id":268,"uris":["http://zotero.org/users/local/i8pMETai/items/KRE3867D"],"uri":["http://zotero.org/users/local/i8pMETai/items/KRE3867D"],"itemData":{"id":268,"type":"article-journal","title":"Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor","container-title":"Journal of Cellular Physiology","page":"36-44","volume":"204","issue":"1","source":"PubMed","abstract":"Axl is a tyrosine kinase receptor and although it is expressed in malignancy such as leukemia, colon cancer, melanoma, endometrial, prostate and thyroid cancers, its role has not been completely elucidated yet and appears to be complex. The ligand of Axl, Gas6, is a 75 KDa multimodular protein with an N-terminal gamma-carboxy-glutamic acid that is essential for binding. Gas6 has a mitogenic effect on several normal cell lines. The receptor Axl is expressed in primary prostate carcinoma and in prostate cancer cell lines as such as PC-3 and DU 145. We demonstrated a mitogenic activity determined by Gas6/Axl interaction in these undifferentiated metastatic human prostatic cancer cell lines. This effect is proportional to Axl expression, not due to inhibition of apoptosis, and induces AKT and MAPK phosphorylation. However, only MEK phosphorylation seems to be essential for growth signaling. Our results suggest that Axl overexpression and activation by Gas6 could be involved in progression of prostate neoplastic disease.","DOI":"10.1002/jcp.20265","ISSN":"0021-9541","note":"PMID: 15605394","journalAbbreviation":"J. Cell. Physiol.","language":"eng","author":[{"family":"Sainaghi","given":"Pier Paolo"},{"family":"Castello","given":"Luigi"},{"family":"Bergamasco","given":"Luca"},{"family":"Galletti","given":"Margherita"},{"family":"Bellosta","given":"Paola"},{"family":"Avanzi","given":"Gian Carlo"}],"issued":{"date-parts":[["2005",7]]},"PMID":"15605394"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (6). AXL was demonstrated to confer resistance to chemotherapies when overexpressed in gastrointestinal stromal tumor  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nSJCR399","properties":{"formattedCitation":"(7)","plainCitation":"(7)"},"citationItems":[{"id":199,"uris":["http://zotero.org/users/local/i8pMETai/items/442HCVSR"],"uri":["http://zotero.org/users/local/i8pMETai/items/442HCVSR"],"itemData":{"id":199,"type":"article-journal","title":"A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors","container-title":"Oncogene","page":"3909-3919","volume":"26","issue":"27","source":"PubMed","abstract":"KIT or alpha-platelet-derived growth factor receptor (alpha-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IM-sensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - AXL - in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.","DOI":"10.1038/sj.onc.1210173","ISSN":"0950-9232","note":"PMID: 17325667","journalAbbreviation":"Oncogene","language":"eng","author":[{"family":"Mahadevan","given":"D."},{"family":"Cooke","given":"L."},{"family":"Riley","given":"C."},{"family":"Swart","given":"R."},{"family":"Simons","given":"B."},{"family":"Della Croce","given":"K."},{"family":"Wisner","given":"L."},{"family":"Iorio","given":"M."},{"family":"Shakalya","given":"K."},{"family":"Garewal","given":"H."},{"family":"Nagle","given":"R."},{"family":"Bearss","given":"D."}],"issued":{"date-parts":[["2007",6,7]]},"PMID":"17325667"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (7) and breast cancer cells ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cVg6DlfQ","properties":{"formattedCitation":"(8)","plainCitation":"(8)"},"citationItems":[{"id":430,"uris":["http://zotero.org/users/local/i8pMETai/items/PRMUEWHT"],"uri":["http://zotero.org/users/local/i8pMETai/items/PRMUEWHT"],"itemData":{"id":430,"type":"article-journal","title":"Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis","container-title":"Oncogene","page":"3442-3455","volume":"28","issue":"39","source":"PubMed","abstract":"Dysregulation of Axl and its ligand growth arrest-specific 6 is implicated in the pathogenesis of several human cancers. In this study, we have used RNAi and monoclonal antibodies to assess further the oncogenic potential of Axl. Here we show that Axl knockdown reduces growth of lung and breast cancer xenograft tumors. Inhibition of Axl expression attenuates breast cancer cell migration and inhibits metastasis to the lung in an orthotopic model, providing the first in vivo evidence that links Axl directly to cancer metastasis. Axl knockdown in endothelial cells impaired tube formation and this effect was additive with anti-vascular endothelial growth factor (VEGF). Further analysis demonstrated that Axl regulates endothelial cell functions by modulation of signaling through angiopoietin/Tie2 and Dickkopf (DKK3) pathways. We have developed and characterized Axl monoclonal antibodies that attenuate non-small cell lung carcinoma xenograft growth by downregulation of receptor expression, reducing tumor cell proliferation and inducing apoptosis. Our data demonstrate that Axl plays multiple roles in tumorigenesis and that therapeutic antibodies against Axl may block Axl functions not only in malignant tumor cells but also in the tumor stroma. The additive effect of Axl inhibition with anti-VEGF suggests that blocking Axl function could be an effective approach for enhancing antiangiogenic therapy.","DOI":"10.1038/onc.2009.212","ISSN":"1476-5594","note":"PMID: 19633687","shortTitle":"Axl as a potential therapeutic target in cancer","journalAbbreviation":"Oncogene","language":"eng","author":[{"family":"Li","given":"Y."},{"family":"Ye","given":"X."},{"family":"Tan","given":"C."},{"family":"Hongo","given":"J.-A."},{"family":"Zha","given":"J."},{"family":"Liu","given":"J."},{"family":"Kallop","given":"D."},{"family":"Ludlam","given":"M. J. C."},{"family":"Pei","given":"L."}],"issued":{"date-parts":[["2009",10,1]]},"PMID":"19633687"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (8). AXL was first cloned from myeloid leukemia cells in 1991 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OIXEu95l","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":137,"uris":["http://zotero.org/users/local/i8pMETai/items/N99FMSVP"],"uri":["http://zotero.org/users/local/i8pMETai/items/N99FMSVP"],"itemData":{"id":137,"type":"article-journal","title":"axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase","container-title":"Molecular and Cellular Biology","page":"5016-5031","volume":"11","issue":"10","source":"PubMed","abstract":"Using a sensitive transfection-tumorigenicity assay, we have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antiphosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type III and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.","ISSN":"0270-7306","note":"PMID: 1656220\nPMCID: PMC361494","journalAbbreviation":"Mol. Cell. Biol.","language":"eng","author":[{"family":"O'Bryan","given":"J. P."},{"family":"Frye","given":"R. A."},{"family":"Cogswell","given":"P. C."},{"family":"Neubauer","given":"A."},{"family":"Kitch","given":"B."},{"family":"Prokop","given":"C."},{"family":"Espinosa","given":"R."},{"family":"Le Beau","given":"M. M."},{"family":"Earp","given":"H. S."},{"family":"Liu","given":"E. T."}],"issued":{"date-parts":[["1991",10]]},"PMID":"1656220","PMCID":"PMC361494"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (9). No crystal structure for Axl catalytic domain has been reported. Just the extracellular Ig-like domain was crystallized as fragments in complex with Gas6 in 2006  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Yxi4J2Zz","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":378,"uris":["http://zotero.org/users/local/i8pMETai/items/G3KQSMBU"],"uri":["http://zotero.org/users/local/i8pMETai/items/G3KQSMBU"],"itemData":{"id":378,"type":"article-journal","title":"Structural basis for Gas6�Axl signalling","container-title":"The EMBO Journal","page":"80-87","volume":"25","issue":"1","source":"emboj.embopress.org","abstract":"Receptor tyrosine kinases of the Axl family are activated by the vitamin K dependent protein Gas6. Axl signalling plays important roles in cancer, spermatogenesis, immunity, and platelet function. The crystal structure at 3.3 � resolution of a minimal human Gas6/Axl complex reveals an assembly of 2:2 stoichiometry, in which the two immunoglobulin like domains of the Axl ectodomain are crosslinked by the first laminin G like domain of Gas6, with no direct Axl/Axl or Gas6/Gas6 contacts. There are two distinct Gas6/Axl contacts of very different size, both featuring interactions between edge � strands. Structure based mutagenesis, protein binding assays and receptor activation experiments demonstrate that both the major and minor Gas6 binding sites are required for productive transmembrane signalling. Gas6 mediated Axl dimerisation is likely to occur in two steps, with a high affinity 1:1 Gas6/Axl complex forming first. Only the minor Gas6 binding site is highly conserved in the other Axl family receptors, Sky/Tyro3 and Mer. Specificity at the major contact is suggested to result from the segregation of charged and apolar residues to opposite faces of the newly formed � sheet.","DOI":"10.1038/sj.emboj.7600912","ISSN":"0261-4189, 1460-2075","note":"PMID: 16362042","language":"en","author":[{"family":"Sasaki","given":"Takako"},{"family":"Knyazev","given":"Pjotr G."},{"family":"Clout","given":"Naomi J."},{"family":"Cheburkin","given":"Yuri"},{"family":"G�hring","given":"Walter"},{"family":"Ullrich","given":"Axel"},{"family":"Timpl","given":"Rupert"},{"family":"Hohenester","given":"Erhard"}],"issued":{"date-parts":[["2006",1,11]]},"PMID":"16362042"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (10).  
During the last decades, inhibition of AXL tyrosine kinases has emerged as an important approach for cancer therapy. Until this date, no inhibitor was clearly designed and marketed to inhibit AXL.  However, Some clinical molecules, developed to inhibit other kinases, were evaluated against AXL given its interest, but these molecules continue to be inadequate having either limited efficacy, prohibitive toxicities or often exhibit less potency for AXL. All these are due to the similarity of the kinases catalytic domains, to which classical ATP competitive inhibitors (type I and II) tend to bind, particularly, with c-MET and MERTK kinases. Recently, the first AXL specific small molecule inhibitor, BGB324 originally discovered by BergenBio Company as R-428, entered phase 1 clinical trials  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ByN28Oz4","properties":{"formattedCitation":"(11)","plainCitation":"(11)"},"citationItems":[{"id":443,"uris":["http://zotero.org/users/local/i8pMETai/items/PVFQH3MR"],"uri":["http://zotero.org/users/local/i8pMETai/items/PVFQH3MR"],"itemData":{"id":443,"type":"article-journal","title":"First Axl inhibitor enters clinical trials","container-title":"Nature Biotechnology","page":"775-776","volume":"31","issue":"9","source":"www.nature.com","abstract":"On June 19, BergenBio disclosed that BGB324, which it bills as a first-in-class Axl kinase inhibitor, entered phase 1 clinical trials. The move marks an important milestone in the emergence of a highly�","DOI":"10.1038/nbt0913-775a","ISSN":"1087-0156","journalAbbreviation":"Nat Biotech","language":"en","author":[{"family":"Sheridan","given":"Cormac"}],"issued":{"date-parts":[["2013",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (11).
Thus, there is a need for other therapies that can desactivate AXL kinase and  keep the cancer in remission and increase survival. Previous studies have focused on the anticancer effects of natural products, for designing novel molecules ATP competitives with low toxicity.
Curcumin, has been shown to be effective against different cancers  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5nxuQM4K","properties":{"formattedCitation":"(12)","plainCitation":"(12)"},"citationItems":[{"id":201,"uris":["http://zotero.org/users/local/i8pMETai/items/PTNE3RAI"],"uri":["http://zotero.org/users/local/i8pMETai/items/PTNE3RAI"],"itemData":{"id":201,"type":"article-journal","title":"Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate","container-title":"Cancer Research","page":"5941-5946","volume":"48","issue":"21","source":"PubMed","abstract":"The effects of topically applied curcumin, chlorogenic acid, caffeic acid, and ferulic acid on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors were evaluated in female CD-1 mice. Topical application of 0.5, 1, 3, or 10 mumol of curcumin inhibited by 31, 46, 84, or 98%, respectively, the induction of epidermal ornithine decarboxylase activity by 5 nmol of TPA. In an additional study, the topical application of 10 mumol of curcumin, chlorogenic acid, caffeic acid, or ferulic acid inhibited by 91, 25, 42, or 46%, respectively, the induction of ornithine decarboxylase activity by 5 nmol of TPA. The topical application of 10 mumol of curcumin together with 2 or 5 nmol of TPA inhibited the TPA-dependent stimulation of the incorporation of [3H]-thymidine into epidermal DNA by 49 or 29%, respectively, whereas lower doses of curcumin had little or no effect. Chlorogenic acid, caffeic acid, and ferulic acid were less effective than curcumin as inhibitors of the TPA-dependent stimulation of DNA synthesis. Topical application of 1, 3, or 10 mumol of curcumin together with 5 nmol of TPA twice weekly for 20 weeks to mice previously initiated with 7,12-dimethylbenz[a]anthracene inhibited the number of TPA-induced tumors per mouse by 39, 77, or 98%, respectively. Similar treatment of mice with 10 mumol of chlorogenic acid, caffeic acid, or ferulic acid together with 5 nmol of TPA inhibited the number of TPA-induced tumors per mouse by 60, 28, or 35%, respectively, and higher doses of the phenolic acids caused a more pronounced inhibition of tumor promotion. The possibility that curcumin could inhibit the action of arachidonic acid was evaluated by studying the effect of curcumin on arachidonic acid-induced edema of mouse ears. The topical application of 3 or 10 mumol of curcumin 30 min before the application of 1 mumol of arachidonic acid inhibited arachidonic acid-induced edema by 33 or 80%, respectively.","ISSN":"0008-5472","note":"PMID: 3139287","journalAbbreviation":"Cancer Res.","language":"eng","author":[{"family":"Huang","given":"M. T."},{"family":"Smart","given":"R. C."},{"family":"Wong","given":"C. Q."},{"family":"Conney","given":"A. H."}],"issued":{"date-parts":[["1988",11,1]]},"PMID":"3139287"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (12) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"CGoNl7gS","properties":{"formattedCitation":"(13)","plainCitation":"(13)"},"citationItems":[{"id":205,"uris":["http://zotero.org/users/local/i8pMETai/items/KNUVIBC2"],"uri":["http://zotero.org/users/local/i8pMETai/items/KNUVIBC2"],"itemData":{"id":205,"type":"article-journal","title":"Antitumor, anti-invasion, and antimetastatic effects of curcumin","container-title":"Advances in Experimental Medicine and Biology","page":"173-184","volume":"595","source":"PubMed","abstract":"Curcumin was found to be cytotoxic in nature to a wide variety of tumor cell lines of different tissue origin. The action of curcumin is dependent on with the cell type, the concentration of curcumin (IC50: 2-40 microg/mL), and the time of the treatment. The major mechanism by which curcumin induces cytotoxicity is the induction of apoptosis. Curcumin decreased the expression of antiapoptotic members of the Bcl-2 family and elevated the expression of p53, Bax, procaspases 3, 8, and 9. Curcumin prevents the entry of nuclear factor KB (NF-KB) into the nucleus there by decreasing the expression of cell cycle regulatory proteins and survival factors such as Bcl-2 and survivin. Curcumin arrested the cell cycle by preventing the expression of cyclin D1, cdk-1 and cdc-25. Curcumin inhibited the growth of transplantable tumors in different animal models and increased the life span of tumor-harboring animals. Curcumin inhibits metastasis of tumor cells as shown in in vitro as well as in vivo models, and the possible mechanism is the inhibition of matrix metalloproteases. Curcumin was found to suppress the expression of cyclooxygenase-2, vascular endothelial growth factor, and intercellular adhesion molecule- and elevated the expression of antimetastatic proteins, the tissue inhibitor of metalloproteases-2, nonmetastatic gene 23, and Ecadherin. These results indicate that curcumin acts at various stages of tumor cell progression.","ISSN":"0065-2598","note":"PMID: 17569210","journalAbbreviation":"Adv. Exp. Med. Biol.","language":"eng","author":[{"family":"Kuttan","given":"Girija"},{"family":"Kumar","given":"Kuzhuvelil B. Hari"},{"family":"Guruvayoorappan","given":"Chandrasekharan"},{"family":"Kuttan","given":"Ramadasan"}],"issued":{"date-parts":[["2007"]]},"PMID":"17569210"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (13) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Aa4rt27a","properties":{"formattedCitation":"(14)","plainCitation":"(14)"},"citationItems":[{"id":207,"uris":["http://zotero.org/users/local/i8pMETai/items/A4FDN4DF"],"uri":["http://zotero.org/users/local/i8pMETai/items/A4FDN4DF"],"itemData":{"id":207,"type":"article-journal","title":"Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways","container-title":"Molecular Pharmacology","page":"29-39","volume":"72","issue":"1","source":"PubMed","abstract":"Autophagy is a response of cancer cells to various anticancer therapies. It is designated as programmed cell death type II and characterized by the formation of autophagic vacuoles in the cytoplasm. The Akt/mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathways are two major pathways that regulate autophagy induced by nutrient starvation. These pathways are also frequently associated with oncogenesis in a variety of cancer cell types, including malignant gliomas. However, few studies have examined both of these signal pathways in the context of anticancer therapy-induced autophagy in cancer cells, and the effect of autophagy on cell death remains unclear. Here, we examined the anticancer efficacy and mechanisms of curcumin, a natural compound with low toxicity in normal cells, in U87-MG and U373-MG malignant glioma cells. Curcumin induced G(2)/M arrest and nonapoptotic autophagic cell death in both cell types. It inhibited the Akt/mTOR/p70S6K pathway and activated the ERK1/2 pathway, resulting in induction of autophagy. It is interesting that activation of the Akt pathway inhibited curcumin-induced autophagy and cytotoxicity, whereas inhibition of the ERK1/2 pathway inhibited curcumin-induced autophagy and induced apoptosis, thus resulting in enhanced cytotoxicity. These results imply that the effect of autophagy on cell death may be pathway-specific. In the subcutaneous xenograft model of U87-MG cells, curcumin inhibited tumor growth significantly (P < 0.05) and induced autophagy. These results suggest that curcumin has high anticancer efficacy in vitro and in vivo by inducing autophagy and warrant further investigation toward possible clinical application in patients with malignant glioma.","DOI":"10.1124/mol.106.033167","ISSN":"0026-895X","note":"PMID: 17395690","shortTitle":"Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy","journalAbbreviation":"Mol. Pharmacol.","language":"eng","author":[{"family":"Aoki","given":"Hiroshi"},{"family":"Takada","given":"Yasunari"},{"family":"Kondo","given":"Seiji"},{"family":"Sawaya","given":"Raymond"},{"family":"Aggarwal","given":"Bharat B."},{"family":"Kondo","given":"Yasuko"}],"issued":{"date-parts":[["2007",7]]},"PMID":"17395690"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (14) in both in vitro and in vivo assays through a variety of mechanisms  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"g40dGOgD","properties":{"formattedCitation":"(15)","plainCitation":"(15)"},"citationItems":[{"id":211,"uris":["http://zotero.org/users/local/i8pMETai/items/CFPX8223"],"uri":["http://zotero.org/users/local/i8pMETai/items/CFPX8223"],"itemData":{"id":211,"type":"article-journal","title":"Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins","container-title":"Cancer Letters","page":"199-225","volume":"269","issue":"2","source":"PubMed","abstract":"Because most cancers are caused by dysregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. Curcumin, a yellow coloring agent in turmeric, has been shown to interact with a wide variety of proteins and modify their expression and activity. These include inflammatory cytokines and enzymes, transcription factors, and gene products linked with cell survival, proliferation, invasion, and angiogenesis. Curcumin has been found to inhibit the proliferation of various tumor cells in culture, prevents carcinogen-induced cancers in rodents, and inhibits the growth of human tumors in xenotransplant or orthotransplant animal models either alone or in combination with chemotherapeutic agents or radiation. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. These aspects of curcumin are discussed further in detail in this review.","DOI":"10.1016/j.canlet.2008.03.009","ISSN":"1872-7980","note":"PMID: 18479807","journalAbbreviation":"Cancer Lett.","language":"eng","author":[{"family":"Kunnumakkara","given":"Ajaikumar B."},{"family":"Anand","given":"Preetha"},{"family":"Aggarwal","given":"Bharat B."}],"issued":{"date-parts":[["2008",10,8]]},"PMID":"18479807"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (15) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lhKRPDna","properties":{"formattedCitation":"(16)","plainCitation":"(16)"},"citationItems":[{"id":213,"uris":["http://zotero.org/users/local/i8pMETai/items/ZPUQF8JB"],"uri":["http://zotero.org/users/local/i8pMETai/items/ZPUQF8JB"],"itemData":{"id":213,"type":"article-journal","title":"Multiple molecular targets in cancer chemoprevention by curcumin","container-title":"The AAPS journal","page":"E443-449","volume":"8","issue":"3","source":"PubMed","abstract":"Carcinogenesis encompasses 3 closely associated stages: initiation, progression, and promotion. Phytochemicals are nonnutritive components of plants that are currently being studied in chemoprevention of various diseases for their pleiotropic effects and nontoxicity. Cancer chemoprevention involves the use of either natural or synthetic chemicals to prevent the initiation, promotion, or progression of cancer. Curcumin is the active constituent of turmeric, which is widely used as a spice in Indian cooking. It has been shown to possess anti-inflammatory, antioxidant, and antitumor properties. Curcumin has also been shown to be beneficial in all 3 stages of carcinogenesis. Much of its beneficial effect is found to be due to its inhibition of the transcription factor nuclear factor kappa B (NF-kappaB) and subsequent inhibition of proinflammatory pathways. This review summarizes the inhibition of NF-kappaB by curcumin and describes the recently identified molecular targets of curcumin. It is hoped that continued research will lead to development of curcumin as an anticancer agent.","DOI":"10.1208/aapsj080352","ISSN":"1550-7416","note":"PMID: 17025261\nPMCID: PMC2761050","journalAbbreviation":"AAPS J","language":"eng","author":[{"family":"Thangapazham","given":"Rajesh L."},{"family":"Sharma","given":"Anuj"},{"family":"Maheshwari","given":"Radha K."}],"issued":{"date-parts":[["2006",7,7]]},"PMID":"17025261","PMCID":"PMC2761050"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (16). In addition, human clinical trials did not demonstrate any toxicity for curcumin at doses up to 10g/day  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qBC6sBRC","properties":{"formattedCitation":"(17)","plainCitation":"(17)"},"citationItems":[{"id":242,"uris":["http://zotero.org/users/local/i8pMETai/items/RVKA23QW"],"uri":["http://zotero.org/users/local/i8pMETai/items/RVKA23QW"],"itemData":{"id":242,"type":"article-journal","title":"Anticancer potential of curcumin: preclinical and clinical studies","container-title":"Anticancer Research","page":"363-398","volume":"23","issue":"1A","source":"PubMed","abstract":"Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF-kappa B, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies.","ISSN":"0250-7005","note":"PMID: 12680238","shortTitle":"Anticancer potential of curcumin","journalAbbreviation":"Anticancer Res.","language":"eng","author":[{"family":"Aggarwal","given":"Bharat B."},{"family":"Kumar","given":"Anushree"},{"family":"Bharti","given":"Alok C."}],"issued":{"date-parts":[["2003",2]]},"PMID":"12680238"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (17). Curcumin, isolated from turmeric Curcuma longa contains curcumin as major component(77%) but it also contains demethoxycurcumin (DMC) (17%) and bisdemethoxycurcumin (BDMC) (3%) that have a remarkable anti- carcinogenisis effect. A study showed that demethoxycurcumin induced the G2/M step of cellular cycle arrest in human glioma U87cells  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xjNoGt4j","properties":{"formattedCitation":"(18)","plainCitation":"(18)"},"citationItems":[{"id":334,"uris":["http://zotero.org/users/local/i8pMETai/items/8R33GN3F"],"uri":["http://zotero.org/users/local/i8pMETai/items/8R33GN3F"],"itemData":{"id":334,"type":"article-journal","title":"Demethoxycurcumin induces Bcl-2 mediated G2/M arrest and apoptosis in human glioma U87 cells","container-title":"Biochemical and Biophysical Research Communications","page":"420-425","volume":"384","issue":"4","source":"PubMed","abstract":"Docking analysis of curcumin (C1), demethoxycurcumin (C2) and bisdemethoxycurcumin (C3) with Bcl-2 illustrated that among the three curcuminoids, C2 binds more efficiently into its putative active site. C1, C2 and C3 were purified from turmeric rhizomes to demonstrate the molecular mechanism of their anticancer activity on human glioma U87 cells. Human glioma U87 cells treated with curcuminoids resulted in activation of Bcl-2 mediated G2 checkpoint, which was associated with the induction of G2/M arrest and apoptosis. The binding of C1, C2 and C3 with Bcl-2 protein was confirmed with circular dichroism (CD) spectroscopy. Present work revealed that C2 induced Bcl-2 mediated G2/M arrest and apoptosis most effectively.","DOI":"10.1016/j.bbrc.2009.04.149","ISSN":"1090-2104","note":"PMID: 19422808","journalAbbreviation":"Biochem. Biophys. Res. Commun.","language":"eng","author":[{"family":"Luthra","given":"Pratibha Mehta"},{"family":"Kumar","given":"Rakesh"},{"family":"Prakash","given":"Amresh"}],"issued":{"date-parts":[["2009",7,10]]},"PMID":"19422808"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (18). In another study, BDMC was observed to suppress the growth and activity in human adenogastric carcinoma ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5V0Lm9kj","properties":{"formattedCitation":"(19)","plainCitation":"(19)"},"citationItems":[{"id":226,"uris":["http://zotero.org/users/local/i8pMETai/items/9N7IZRQP"],"uri":["http://zotero.org/users/local/i8pMETai/items/9N7IZRQP"],"itemData":{"id":226,"type":"article-journal","title":"Bisdemethoxycurcumin attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction.","container-title":"Oncology letters","page":"270-274","volume":"9","issue":"1","source":"europepmc.org","abstract":"Abstract: Bisdemethoxycurcumin (BDMC) is a demethoxy derivative of curcumin. In this study, a human gastric adenocarcinoma xenograft model was generated in...","DOI":"10.3892/ol.2014.2685","ISSN":"1792-1074","journalAbbreviation":"Oncol Lett","language":"eng","author":[{"family":"C","given":"Luo"},{"family":"Z","given":"Du"},{"family":"X","given":"Wei"},{"family":"G","given":"Chen"},{"family":"Z","given":"Fu"}],"issued":{"date-parts":[["2015",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (19).
Here, we focused on examining the interactions between curcumin as well as DMC and BDMC with AXL domain kinase using in silico appraoch and molecular docking.This study could be applied to develop new potential AXL inhibitors ATP competitives from curcumin and natural derivatives in the future. Since no data are available on AXL crystal structure. Herein we used homology modeling to this end.
Materials and methods
AXL kinase homology modeling 
We used the Swiss model server  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OwZsL9D7","properties":{"formattedCitation":"(20)","plainCitation":"(20)"},"citationItems":[{"id":275,"uris":["http://zotero.org/users/local/i8pMETai/items/B6HMGRJJ"],"uri":["http://zotero.org/users/local/i8pMETai/items/B6HMGRJJ"],"itemData":{"id":275,"type":"article-journal","title":"The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling","container-title":"Bioinformatics (Oxford, England)","page":"195-201","volume":"22","issue":"2","source":"PubMed","abstract":"MOTIVATION: Homology models of proteins are of great interest for planning and analysing biological experiments when no experimental three-dimensional structures are available. Building homology models requires specialized programs and up-to-date sequence and structural databases. Integrating all required tools, programs and databases into a single web-based workspace facilitates access to homology modelling from a computer with web connection without the need of downloading and installing large program packages and databases.\nRESULTS: SWISS-MODEL workspace is a web-based integrated service dedicated to protein structure homology modelling. It assists and guides the user in building protein homology models at different levels of complexity. A personal working environment is provided for each user where several modelling projects can be carried out in parallel. Protein sequence and structure databases necessary for modelling are accessible from the workspace and are updated in regular intervals. Tools for template selection, model building and structure quality evaluation can be invoked from within the workspace. Workflow and usage of the workspace are illustrated by modelling human Cyclin A1 and human Transmembrane Protease 3.\nAVAILABILITY: The SWISS-MODEL workspace can be accessed freely at http://swissmodel.expasy.org/workspace/","DOI":"10.1093/bioinformatics/bti770","ISSN":"1367-4803","note":"PMID: 16301204","shortTitle":"The SWISS-MODEL workspace","journalAbbreviation":"Bioinformatics","language":"eng","author":[{"family":"Arnold","given":"Konstantin"},{"family":"Bordoli","given":"Lorenza"},{"family":"Kopp","given":"J�rgen"},{"family":"Schwede","given":"Torsten"}],"issued":{"date-parts":[["2006",1,15]]},"PMID":"16301204"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (20) to bluit the AXL model by homology modeling, a proto-oncogene tyrosine-protein kinase MER( MERTK PDB code:3BRB, resolution 1.9�) was used as template.
The template was selected based on sequence identity and the coverage of the sequence obtained by alignement using Basic Local Alignment SearchTool  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7fnPZrsP","properties":{"formattedCitation":"(21)","plainCitation":"(21)"},"citationItems":[{"id":328,"uris":["http://zotero.org/users/local/i8pMETai/items/FCRNBKJJ"],"uri":["http://zotero.org/users/local/i8pMETai/items/FCRNBKJJ"],"itemData":{"id":328,"type":"article-journal","title":"Basic local alignment search tool","container-title":"Journal of Molecular Biology","page":"403-410","volume":"215","issue":"3","source":"PubMed","abstract":"A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score. Recent mathematical results on the stochastic properties of MSP scores allow an analysis of the performance of this method as well as the statistical significance of alignments it generates. The basic algorithm is simple and robust; it can be implemented in a number of ways and applied in a variety of contexts including straightforward DNA and protein sequence database searches, motif searches, gene identification searches, and in the analysis of multiple regions of similarity in long DNA sequences. In addition to its flexibility and tractability to mathematical analysis, BLAST is an order of magnitude faster than existing sequence comparison tools of comparable sensitivity.","DOI":"10.1016/S0022-2836(05)80360-2","ISSN":"0022-2836","note":"PMID: 2231712","journalAbbreviation":"J. Mol. Biol.","language":"eng","author":[{"family":"Altschul","given":"S. F."},{"family":"Gish","given":"W."},{"family":"Miller","given":"W."},{"family":"Myers","given":"E. W."},{"family":"Lipman","given":"D. J."}],"issued":{"date-parts":[["1990",10,5]]},"PMID":"2231712"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (21) ( HYPERLINK "http://blast.ncbi.nlm.nih.gov/Blast.cgi). AXL" http://blast.ncbi.nlm.nih.gov/Blast.cgi). AXL and MERTK sequences were obtained from UniProt database (ID: P30530; ID:  HYPERLINK "http://www.uniprot.org/uniprot/Q12866" Q12866 respectively) (www.Uniprot.org) 
Model validation
Structural refinement was further assessed by Structural Analysis and Verification Server (version3) (http://nihserver.mbi.ucla.edu/SAVES/). This meta server runs six programs for checking and validating protein structures. Verify3D analyzes the compatibility of an atomic model (3D) with its own amino acid sequence (1D) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"T4weRVhk","properties":{"formattedCitation":"(22)","plainCitation":"(22)"},"citationItems":[{"id":279,"uris":["http://zotero.org/users/local/i8pMETai/items/252J7K97"],"uri":["http://zotero.org/users/local/i8pMETai/items/252J7K97"],"itemData":{"id":279,"type":"article-journal","title":"VERIFY3D: assessment of protein models with three-dimensional profiles","container-title":"Methods in Enzymology","page":"396-404","volume":"277","source":"PubMed","ISSN":"0076-6879","note":"PMID: 9379925","shortTitle":"VERIFY3D","journalAbbreviation":"Meth. Enzymol.","language":"eng","author":[{"family":"Eisenberg","given":"D."},{"family":"L�thy","given":"R."},{"family":"Bowie","given":"J. U."}],"issued":{"date-parts":[["1997"]]},"PMID":"9379925"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (22). The structure was analyzed by Ramachandran�s plot using PROCHECK software  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xfQgO7zE","properties":{"formattedCitation":"(23)","plainCitation":"(23)"},"citationItems":[{"id":281,"uris":["http://zotero.org/users/local/i8pMETai/items/ZUQDGC5A"],"uri":["http://zotero.org/users/local/i8pMETai/items/ZUQDGC5A"],"itemData":{"id":281,"type":"article-journal","title":"AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR","container-title":"Journal of biomolecular NMR","page":"477-486","volume":"8","issue":"4","source":"PubMed","abstract":"The AQUA and PROCHECK-NMR programs provide a means of validating the geometry and restraint violations of an ensemble of protein structures solved by solution NMR. The outputs include a detailed breakdown of the restraint violations, a number of plots in PostScript format and summary statistics. These various analyses indicate both the degree of agreement of the model structures with the experimental dat, and the quality of their geometrical properties. They are intended to be of use both to support ongoing NMR structure determination and in the validation of the final results.","ISSN":"0925-2738","note":"PMID: 9008363","shortTitle":"AQUA and PROCHECK-NMR","journalAbbreviation":"J. Biomol. NMR","language":"eng","author":[{"family":"Laskowski","given":"R. A."},{"family":"Rullmannn","given":"J. A."},{"family":"MacArthur","given":"M. W."},{"family":"Kaptein","given":"R."},{"family":"Thornton","given":"J. M."}],"issued":{"date-parts":[["1996",12]]},"PMID":"9008363"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (23).
Active site validation
In order to evaluate the model catalytic cavity and critical residues involved in AXL active site, molecular docking studies of ATP with the AXL model was performed with AutoDock vina 4.0  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7eU2heoY","properties":{"formattedCitation":"(24)","plainCitation":"(24)"},"citationItems":[{"id":322,"uris":["http://zotero.org/users/local/i8pMETai/items/KPH66X7B"],"uri":["http://zotero.org/users/local/i8pMETai/items/KPH66X7B"],"itemData":{"id":322,"type":"article-journal","title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","container-title":"Journal of Computational Chemistry","page":"455-461","volume":"31","issue":"2","source":"PubMed","abstract":"AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user.","DOI":"10.1002/jcc.21334","ISSN":"1096-987X","note":"PMID: 19499576\nPMCID: PMC3041641","shortTitle":"AutoDock Vina","journalAbbreviation":"J Comput Chem","language":"eng","author":[{"family":"Trott","given":"Oleg"},{"family":"Olson","given":"Arthur J."}],"issued":{"date-parts":[["2010",1,30]]},"PMID":"19499576","PMCID":"PMC3041641"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (24). The best conformation with best binding affinity in kcal/mol was selected.



Docking approach
Binding mode and selectivity of AXL kinase with curcumin and naturals derivatives were studied by AutoDock vina 4.0  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ozuONqCg","properties":{"formattedCitation":"(24)","plainCitation":"(24)"},"citationItems":[{"id":322,"uris":["http://zotero.org/users/local/i8pMETai/items/KPH66X7B"],"uri":["http://zotero.org/users/local/i8pMETai/items/KPH66X7B"],"itemData":{"id":322,"type":"article-journal","title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","container-title":"Journal of Computational Chemistry","page":"455-461","volume":"31","issue":"2","source":"PubMed","abstract":"AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user.","DOI":"10.1002/jcc.21334","ISSN":"1096-987X","note":"PMID: 19499576\nPMCID: PMC3041641","shortTitle":"AutoDock Vina","journalAbbreviation":"J Comput Chem","language":"eng","author":[{"family":"Trott","given":"Oleg"},{"family":"Olson","given":"Arthur J."}],"issued":{"date-parts":[["2010",1,30]]},"PMID":"19499576","PMCID":"PMC3041641"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (24)  which required  the ligand and receptor in pdbqt format
and the configuration file as txt format. The Autodock Vina also produces files containing the ligands docked pose as output wich contain the score of the binding affinity, these files were analyzed to study interactions and binding energy of the docking. The results were visualized using Pymol molecular viewer v.1.7.4 h HYPERLINK "http://www.schrodinger.com/pymol/" ttp://www.schrodinger.com/pymol/.
Ligands collection and preparation  
Curcumin and two natural analogues namly demetoxycurcumin (DMC), bisdemethoxycurcumin (BDMC) coumponds were selected on the basis of their anticarcinogenic activity experimentally  proved and metabolic stability in comparaison with native curcumin. The strucutres of these coumponds were downloaded from NCBI Pubchem (CID:96516; 5469424; 5315472 respectively) in PDB format. The Pymol was used to verify the presence or absence of hydrogen, the stereochemistry of chiral carbons, number of rotable bonds, number of hydrogen acceptors and donors.
For all ligands, Gasteiger charges were designated and the torsions for ligands were permitted to rotate during docking procedure using Autodock tools v.1.5.6. The ligands were saved in pdbqt format.
Target preparation 
The receptor was prepared in Autodock tools v.1.5.6, polar hydrogens were assigned to the receptor, the grid-box was centered around the AXL active site, the dimensions were set at 30,30,30 � (x, y and z) consisting of active site residues within the box. The receptor was saved in pdbqt format.
Resultats 
Sequence analysis
The amino acid sequence of AXL catalytic domain was retrieved from the Uniprot database. The selected sequence for physiochemical analysis and 3D modeling is given in Figure 1. 
Sequence alignment by BLAST showed, 70% identity between a sequence of the AXL catalytic domain and the template.
3D structure prediction and model validation
The 3D structure prediction (Figure 2) was carried out by alignment of target sequences with template structure (PDB ID 3BRB), using a Swiss Model Server. Figure3 presents the supperposition between the constructed model and the template complexed with ADP ligand. Figure 4 shows the VERIFY-3D graph determining that 95.96% of AXL residues have an average score of 3D-1De"0.2 confirming the compatibility of the 3D structure and the primary sequence of AXL.  
The sterochemical quality and accuracy of the predicted model was evaluated after the refinement process using the Ramachandran plot calculated with the PROCHECK program  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"doTv5iGf","properties":{"formattedCitation":"(23)","plainCitation":"(23)"},"citationItems":[{"id":281,"uris":["http://zotero.org/users/local/i8pMETai/items/ZUQDGC5A"],"uri":["http://zotero.org/users/local/i8pMETai/items/ZUQDGC5A"],"itemData":{"id":281,"type":"article-journal","title":"AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR","container-title":"Journal of biomolecular NMR","page":"477-486","volume":"8","issue":"4","source":"PubMed","abstract":"The AQUA and PROCHECK-NMR programs provide a means of validating the geometry and restraint violations of an ensemble of protein structures solved by solution NMR. The outputs include a detailed breakdown of the restraint violations, a number of plots in PostScript format and summary statistics. These various analyses indicate both the degree of agreement of the model structures with the experimental dat, and the quality of their geometrical properties. They are intended to be of use both to support ongoing NMR structure determination and in the validation of the final results.","ISSN":"0925-2738","note":"PMID: 9008363","shortTitle":"AQUA and PROCHECK-NMR","journalAbbreviation":"J. Biomol. NMR","language":"eng","author":[{"family":"Laskowski","given":"R. A."},{"family":"Rullmannn","given":"J. A."},{"family":"MacArthur","given":"M. W."},{"family":"Kaptein","given":"R."},{"family":"Thornton","given":"J. M."}],"issued":{"date-parts":[["1996",12]]},"PMID":"9008363"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (23). The � and � distributions of the Ramachandran plots of non-glycine, non-proline residues are represented in Figure5, showing 93.3% (252 amino-acids) of residues in the favoured regions, 6.3% (17amino acids) in  allowed region and 0.4 %  (1 amino acids) in outlier region. Figure 6 shows the residue phenylalanine (Phe613) found in the outlier region is at very long distances from the pocket suggesting that this amino acid is structurally and functionally irrelevant to the ligand-binding site.
Active site validation by ATP
Among the nine conformations results of docking between AXL kinase and ATP, we have selected the best binding position with an energy of -8.7 kcal /mol. Figure 7 shows that AXL kinase interacts with ATP principally by seven hydrogen bonds which are summarized in TableI. 
Interaction betwenn AXL and curcumin compounds
The 2D structures of curcumin compounds used in this study are illustrated in Figure8. As showed in Figure 9(a,b), the three compounds occupied the common binding site of the AXL kinase. The binding energy of AXL- curcumin, AXL-DMC and AXL-BDMC complexes was respectivelly -9.8 kcal/mol, -9.4 kcal/mol and -9.0 kcal/mol. Table II ressemble the binding affinity and the hydrogen bond distances of the key residues that interact with inhibitors. 
Figures 10 (a, b and c) shows that all curcuminoids formed a hydrogen bonds with the same residues, Met 623, Lys 567, Ala 689 and Asp 690. The Met 623 of the hinge region makes a hydrogen bonds of 2.3�, 2.7� and 2.4� between their nitrogen backbone with curcumin, DMC and BDMC respectivelly.The Lys 567, one of the binding site key residues of ATP, interacts with curcuminoid compounds, the shorter one have a distance of 1.3 � in their interaction with DMC.The shorter distance between Ala 689 of the activation loop and curcumin coumpond was 2.5 �. Furthermore, the three compounds possess a hydrogen bond with DFG motif by their Asparatic acid residue. The hydrogen bonds were created between the side chain of Asp690 and curcumin, DMC and BDMC have a distance of 3.12�, 3.4� and 3.06� respectively.

Discussion
In this paper, we used the in Silico approach and molecular docking to explain the binding mechanism of curcumin and its natural derivatives (DMC, BDMC) to the AXL kinase. We generated a model of AXL kinase using the MERTK as a template for the Swiss Model software and the model was evaluated by Verrify 3D and PROCHECK programs.
The model validation indicated the acceptable quality of the structural model with 99.6% of the model�s torsion angles in favorable positions. The molecular docking did confirm that the ATP molecule is positioned in their AXL kinase binding site. 
Thereafter, we studied the curcuminoids interaction with the AXL kinase to demonstrate if these molecules hold a position inside of the ATP binding site, the results obtained from the molecular docking demonstrated that the selected phytoconstituents are positioned into the active cavity of AXL and exhibits good binding mode with AXL. The binding affinity of the curcuminoids with AXL is well above that of ATP. The curcuminoids create hydrogen bonds with three of the key residues in ATP binding site. The first one was with Met 623 of the hinge region; the second was with Lys 567 positioned on a �-sheet of N-lobe, and the third with Asp 690 of the DFG-motif. Curcumin was found to bind with the best affinity with AXL than DMC and BMDC.The difference in affinity may be due to the number of methoxy groups on the aromatic rings in the curcuminoids, both natural derivatives are two congeners of curcumin isolated from turmeric, furthermore curcumin has two symmetric phenyl-methoxy groups, DMC contains one and BMDC contains none. This suggests that the phenyl methoxy groups do contribute to the inhibiting power of compounds. Chen and al. demonstrated that the activity is also due to the ortho-methoxy phenolic functionality  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EX13R9tA","properties":{"formattedCitation":"(25)","plainCitation":"(25)"},"citationItems":[{"id":355,"uris":["http://zotero.org/users/local/i8pMETai/items/HB8NWGWP"],"uri":["http://zotero.org/users/local/i8pMETai/items/HB8NWGWP"],"itemData":{"id":355,"type":"article-journal","title":"Curcumin and its analogues as potent inhibitors of low density lipoprotein oxidation: H-atom abstraction from the phenolic groups and possible involvement of the 4-hydroxy-3-methoxyphenyl groups","container-title":"Free Radical Biology and Medicine","page":"526-535","volume":"40","issue":"3","source":"ScienceDirect","abstract":"Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, 1) is a yellow ingredient isolated from turmeric (Curcumin longa). It has been shown to exhibit a variety of biological activities including antioxidative activity. In order to find more active antioxidants with 1 as the lead compound we synthesized curcumin analogues, i.e., 1,7-bis(3,4-dihydroxyphenyl)-1,6-heptadiene-3,5-dione (2), 1-(3,4-dihydroxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (3), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (4), 1,7-bis (4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (5), 1-(3,4-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (6), 1,7-bis(3,4-dimethoxyphenyl)-1,6- heptadiene-3,5-dione (7), 1,7-bis(4-methoxyphenyl)-1,6-heptadiene-3,5-dione (8), and 1,7-diphenyl-1,6-heptadiene-3,5-dione (9). Antioxidative effects of curcumin and its analogues against free radical initiated peroxidation of human low density lipoprotein (LDL) were studied. The peroxidation was initiated either by a water-soluble initiator 2,22 -azobis(2-amidinopropane hydrochloride) (AAPH), or by cupric ion (Cu2+). The reaction kinetics were monitored either by the uptake of oxygen and the depletion of �-tocopherol present in the native LDL, or by the formation of thiobarbituric acid reactive substances. Kinetic analysis of the antioxidation process demonstrates that these compounds, except 7, 8, and 9, are effective antioxidants against AAPH- and Cu2+-initiated LDL peroxidation by H-atom abstraction from the phenolic groups. Compounds 2 and 3 which bear ortho-diphenoxyl functionality possess significantly higher antioxidant activity than curcumin and other analogues, and the 4-hydroxy-3-methoxyphenyl group also play an important role in the antioxidative activity.","DOI":"10.1016/j.freeradbiomed.2005.09.008","ISSN":"0891-5849","shortTitle":"Curcumin and its analogues as potent inhibitors of low density lipoprotein oxidation","journalAbbreviation":"Free Radical Biology and Medicine","author":[{"family":"Chen","given":"Wei-Feng"},{"family":"Deng","given":"Shui-Ling"},{"family":"Zhou","given":"Bo"},{"family":"Yang","given":"Li"},{"family":"Liu","given":"Zhong-Li"}],"issued":{"date-parts":[["2006"]],"season":"f�vrier"}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (25).
Curcumin, together with demethoxycurcumin and bisdemethoxycurcumin, are the three predominant active compounds derived from the turmeric root. Several reports have shown that curcumin could modulate each stage of cancer such as initiation, promotion and progression ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"r3bXqAxh","properties":{"formattedCitation":"(26)","plainCitation":"(26)"},"citationItems":[{"id":427,"uris":["http://zotero.org/users/local/i8pMETai/items/FFUDXICM"],"uri":["http://zotero.org/users/local/i8pMETai/items/FFUDXICM"],"itemData":{"id":427,"type":"article-journal","title":"Colorectal cancer: chemopreventive role of curcumin and resveratrol","container-title":"Nutrition and Cancer","page":"958-967","volume":"62","issue":"7","source":"PubMed","abstract":"Colorectal cancer (CRC) is a second leading cause of cancer deaths in the Western world. Currently there is no effective treatment except resection at a very early stage with or without chemotherapy. Of various epithelial cancers, CRC in particular has a potential for prevention, since most cancers follow the adenoma-carcinoma sequence, and the interval between detection of an adenoma and its progression to carcinoma is usually about a decade. However no effective chemopreventive agent except COX-2 inhibitors, limited in their scope due to cardiovascular side effects, have shown promise in reducing adenoma recurrence. To this end, natural agents that can target important carcinogenic pathways without demonstrating discernible adverse effects would serve as ideal chemoprevention agents. In this review, we discuss merits of two such naturally occurring dietary agents-curcumin and resveratrol-for chemoprevention of CRC.","DOI":"10.1080/01635581.2010.510259","ISSN":"1532-7914","note":"PMID: 20924971\nPMCID: PMC3837545","shortTitle":"Colorectal cancer","journalAbbreviation":"Nutr Cancer","language":"eng","author":[{"family":"Patel","given":"Vaishali B."},{"family":"Misra","given":"Sabeena"},{"family":"Patel","given":"Bhaumik B."},{"family":"Majumdar","given":"Adhip P. N."}],"issued":{"date-parts":[["2010"]]},"PMID":"20924971","PMCID":"PMC3837545"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (26). Kim K.C et al. indicate that curcumin has inhibitory effects on AXL expression as Gas6-dependent AXL phosphorylation, and AXL promoter activity in non-small cell lung cancer cells  ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"SJYtOgYY","properties":{"formattedCitation":"(27)","plainCitation":"(27)"},"citationItems":[{"id":233,"uris":["http://zotero.org/users/local/i8pMETai/items/SEM3KI6H"],"uri":["http://zotero.org/users/local/i8pMETai/items/SEM3KI6H"],"itemData":{"id":233,"type":"article-journal","title":"Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells","container-title":"International Journal of Oncology","page":"2296-2303","volume":"47","issue":"6","source":"PubMed","abstract":"Lung cancer is still in the first place in terms of both incidence and mortality. In the present study, we demonstrated the effect of curcumin, a phytochemical of the plant Curcuma longa, on expression and activation of Axl receptor tyrosine kinase (RTK) which plays an important role in cell survival, proliferation and anti-apoptosis. Curcumin treatment of non-small cell lung cancer (NSCLC) A549 and H460 cells, was found to decrease Axl protein as well as mRNA levels in a dose- and time-dependent manner. Axl promoter activity was also reduced by curcumin, indicating that curcumin downregulates Axl expression at the transcriptional level. Moreover, Axl phosphorylation in response to binding of its ligand, Gas6, was abrogated by curcumin, suggesting the inhibitory effect of curcumin on Gas6-induced Axl activation. We next found cytotoxic effect of cucumin on both the parental A549 and H460 cells, and their variants which are resistant to cisplatin (A549/CisR and H460/CisR) and paclitaxel (A549/TR and H460/TR). Exposure of these cells to curcumin resulted in dose-dependent decline of cell viability and clonogenic ability. It is further observed that the anti-proliferative effect of curcumin on A549 cells overexpressing Axl protein was reduced, while that on H460 cells transfected Axl specific siRNA was augmented, confirming that curcumin inhibits cell proliferation via downregulation of Axl expression. In addition, curcumin was found to cause the induction of p21, a cyclin-dependent kinase inhibitor, and reduction of X-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic molecule, in parental H460 cells as well as chemoresistant cells, H460/CisR and H460/TR. Taken together, our data imply that Axl RTK is a novel target of curcumin through which it exerts anti-proliferative effect in both parental and chemoresistant NSCLC cells.","DOI":"10.3892/ijo.2015.3216","ISSN":"1791-2423","note":"PMID: 26498137","journalAbbreviation":"Int. J. Oncol.","language":"eng","author":[{"family":"Kim","given":"Kyung-Chan"},{"family":"Baek","given":"Suk-Hwan"},{"family":"Lee","given":"Chuhee"}],"issued":{"date-parts":[["2015",12]]},"PMID":"26498137"}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (27). The present results will be the basis to develop new compounds ATP- competitive more selective and active against AXL kinase, derived from the curcumin molecule. These results encouraged us to perform the ongoing structural-activity relationship studies to evaluate the relationship of the methoxy-groups and the inhibitory effect against AXL.
Conclusion  
Traditionally, the turmeric has been used commonly as a spice in curries to give a specific flavor and yellow color. This phytochimical and it derivatives have also been found to be effective against different cancers. Our results showed that these compounds have a strong binding affinity to the AXL receptor and could be useful as a source of potential therapeutics or lead molecules for prevention or treatment of multiple cancers. Curcumin has a promising cytotoxic effects against cancer cell lines. But,  further clinical research about the toxicity of the molecule is needed to bring in more clarity on  human safety and how their activity could be exercised in vivo after human consumption.
Competing interests
The authors declare that they have no competing interests.
Aknowledgments
This work was carried out under National funding from the Moroccan Ministry of Higher education & Scientific research (PPR program) to AI. This work was also supported by a grant from the NIH for H3Africa BioNet to AI. 













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 and its analogues as potent inhibitors of low density lipoprotein oxidation: H-atom abstraction from the phenolic groups and possible involvement of the 4-hydroxy-3-methoxyphenyl groups. Free Radic Biol Med. 2006 f�vrier;40(3):526�35. 
26. 	Patel VB, Misra S, Patel BB, Majumdar APN. Colorectal cancer: chemopreventive role of curcumin and resveratrol. Nutr Cancer. 2010;62(7):958�67. 
27. 	Kim K-C, Baek S-H, Lee C. Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells. Int J Oncol. 2015 Dec;47(6):2296�303. 

Tables and Figures 
Table I: Molecular docking results of AXL receptor with ATP using Vina docking software.
ResiduesH Bond length (�)Glu 546
Lys 567           
Lys 624
Asp 627
Arg676
Asn677
Asp6903.0
1.9
2.1
2.4
3.3
2.1
3.3
















Table II: The binding affinity and the hydrogen bond distances of the key residues that interact with inhibitors.
Ligands docked
With AXLbinding affinity 
Kcal /molInteraction  amino acid ResiduesH Bond distance
(�)
Curcumin
-9.8Lys567
Met623
Ala689
Asp6902.27
2.30
2.50
3.122
Demetoxycurcumin        (DMC)

-9.4

Lys 567
Met623
Ala689
Asp6901.3
2.7
3.2
3.4
Bisdemethoxy                curcumin
(BDMC)
-9.0Lys 567
Met 623
Ala 689
Asp6902.20
2.40
3.26
3.06













Figures:
Figure1: Amino acid sequence of AXL catalytic domain
Figure2 : Constructed 3D model of AXL receptor generated by Swiss Model Server
Notes: The model is oriented with the N-lobe at the top and the hinge is colored in red. The C-lobe is at the bottom of the figure, the activation loop in cyane, gatekeeper in magentas a the active site is surrounded in yellow
Figure3: Superposition of AXL (green color) and template MERTK(3 BRB) (cyan color), binding the ADP ligand of templete (red color)
Figure4:  VERIFY-3D plot analysis of computed AXL model
Figure5: Ramachandran plot of structural model of AXL 3D

Figure 6: Position of the Phe 613 found in the outlier region in Ramachandran plot.
Note: The AXL model is in green, Phe613 residue is in red, the active site is surrounded in yellow
Figure7:  
Panel a: Hydrogen bonding interactions with AXL and ATP
Abrevation:ATP.Adenosine triphosphate
Panel b: Molecular docking of AXL with ATP in surface view. 
Figure8: 2D Structures of curcumin natural derivatives
Figure9:
Panel a: ligand binding pose of curcumin (yellowcolor), BDMC (green color), and DMC (red color) superimposed  in the active site of AXL 
Panel b: ligand binding pose of curcumin (yellowcolor), BDMC (green color), and DMC (red color) superimposed  in the active site of AXL in surface view

Figure10: 
Panel a: Hydrogen bonded interactions of curcumin against AXL protein
Panel b: Hydrogen bonded interactions of DMC  against AXL protein
Panel c: Hydrogen bonded interactions of BDMC against AXL protein











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