Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Therapeutic Path to Triple Knockout: Investigating the Pan-inhibitory Mechanisms of AKT, CDK9, and TNKS2 by a Novel 2-phenylquinazolinone Derivative in Cancer Therapy- An In-silico Investigation Therapy

Author(s): Xylia Q. Peters, Ghazi Elamin, Aimen Aljoundi, Mohamed Issa Alahmdi, Nader E. Abo-Dya, Peter A. Sidhom, Ahmed M. Tawfeek, Mahmoud A. A. Ibrahim, Opeyemi Soremekun and Mahmoud E. S. Soliman*

Volume 25, Issue 10, 2024

Published on: 12 October, 2023

Page: [1288 - 1303] Pages: 16

DOI: 10.2174/1389201024666230815145001

Price: $65

Abstract

Background: Blocking the oncogenic Wnt//β-catenin pathway has of late been investigated as a viable therapeutic approach in the treatment of cancer. This involves the multi-targeting of certain members of the tankyrase-kinase family; Tankyrase 2 (TNKS2), Protein Kinase B (AKT), and Cyclin- Dependent Kinase 9 (CDK9), which propagate the oncogenic Wnt/β-catenin signalling pathway.

Methods: During a recent investigation, the pharmacological activity of 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one was repurposed to serve as a ‘triple-target’ inhibitor of TNKS2, AKT and CDK9. Yet, the molecular mechanism that surrounds its multi-targeting activity remains unanswered. As such, this study aims to explore the pan-inhibitory mechanism of 2-(4-aminophenyl)-7-chloro-3H-quinazolin- 4-one towards AKT, CDK9, and TNKS2, using in silico techniques.

Results: Results revealed favourable binding affinities of -34.17 kcal/mol, -28.74 kcal/mol, and -27.30 kcal/mol for 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards TNKS2, CDK9, and AKT, respectively. Pan-inhibitory binding of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one is illustrated by close interaction with specific residues on tankyrase-kinase. Structurally, 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one had an impact on the flexibility, solvent-accessible surface area, and stability of all three proteins, which was illustrated by numerous modifications observed in the unbound as well as the bound states of the structures, which evidenced the disruption of their biological function. Prediction of the pharmacokinetics and physicochemical properties of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4- one further established its inhibitory potential, evidenced by the favourable absorption, metabolism, excretion, and minimal toxicity properties.

Conclusion: The following structural insights provide a starting point for understanding the paninhibitory activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one. Determining the criticality of the interactions that exist between the pyrimidine ring and catalytic residues could offer insight into the structure-based design of innovative tankyrase-kinase inhibitors with enhanced therapeutic effects.

Graphical Abstract

[1]
Mandal, R.; Becker, S.; Strebhardt, K. Targeting CDK9 for anti-cancer therapeutics [Internet]. Cancers. Multidisciplinary Digital Publishing Institute, 2021, 13, 2181. Available From: https://www.mdpi.com/2072-6694/13/9/2181/htm accessed on 2022 May 19
[2]
Boffo, S; Damato, A; Alfano, L; Giordano, A. CDK9 inhibitors in acute myeloid leukemia. J. Exp. Clin. Cancer Res. BioMed Central Ltd, 2018, 37
[http://dx.doi.org/10.1186/s13046-018-0704-8]
[3]
Anshabo, A.T.; Bantie, L.; Diab, S.; Lenjisa, J.; Kebede, A.; Long, Y.; Heinemann, G.; Karanjia, J.; Noll, B.; Basnet, S.K.C.; Li, M.; Milne, R.; Albrecht, H.; Wang, S. An orally bioavailable and highly efficacious inhibitor of cdk9/flt3 for the treatment of acute myeloid leukemia. Cancers, 2022, 14(5), 1113. Available From: https://www.mdpi.com/2072-6694/14/5/1113
[http://dx.doi.org/10.3390/cancers14051113] [PMID: 35267421]
[4]
Li, L.; Han, C.; Yu, X.; Shen, J.; Cao, Y. Targeting AraC-resistant acute myeloid leukemia by dual inhibition of CDK9 and Bcl-2: A systematic review and meta-analysis. J. Healthc. Eng., 2022. Available From: https://www.hindawi.com/journals/jhe/2022/2842066/ accessed on 2022 May 17
[http://dx.doi.org/10.1155/2022/2842066]
[5]
Anshabo, A.T.; Milne, R.; Wang, S.; Albrecht, H. CDK9: A comprehensive review of its biology, and its role as a potential target for anti-cancer agents. Frontiers in Oncology. Frontiers Media S.A., 2021; Vol. 11, .
[6]
Martorana, F.; Motta, G.; Pavone, G.; Motta, L.; Stella, S.; Vitale, S.R. AKT inhibitors: New weapons in the fight against breast cancer? Frontiers in Pharmacology. Frontiers Media S.A., 2021; Vol. 12, p. 546.
[7]
Manning, B.D.; Cantley, L.C. AKT/PKB signaling: Navigating downstream. Cell, 2007, 129(7), 1261-1274. Available From: https://www.sciencedirect.com/science/article/pii/S0092867407007751
[http://dx.doi.org/10.1016/j.cell.2007.06.009] [PMID: 17604717]
[8]
Nicholson, K.M.; Anderson, N.G. The protein kinase B/Akt signalling pathway in human malignancy. Cellular Signalling Pergamon, 2002, 381-395. Available From: https://www.sciencedirect.com/science/article/pii/S0898656801002716
[9]
Hemmings, B.A. Akt signaling: Linking membrane events to life and death decisions. Science, 1997, 275(5300), 628-630.
[http://dx.doi.org/10.1126/science.275.5300.628] [PMID: 9019819]
[10]
Yu, L.; Wei, J.; Liu, P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Seminars in Cancer Biology, 2021. Available From: https://www.sciencedirect.com/science/article/pii/S1044579X21001887 accessed on 2022 May 16
[11]
Xie, X.; Shu, R.; Yu, C.; Fu, Z.; Li, Z. Mammalian AKT, the emerging roles on mitochondrial function in diseases. Aging Dis., 2022, 13(1), 157-174. Available From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782557/
[http://dx.doi.org/10.14336/AD.2021.0729] [PMID: 35111368]
[12]
Lin, K.; Lin, J.; Wu, W.I.; Ballard, J.; Lee, B.B.; Gloor, S.L.; Vigers, G.P.A.; Morales, T.H.; Friedman, L.S.; Skelton, N.; Brandhuber, B.J. An ATP-site on-off switch that restricts phosphatase accessibility of Akt. Sci. Signal., 2012, 5(223), ra37.
[http://dx.doi.org/10.1126/scisignal.2002618] [PMID: 22569334]
[13]
Altomare, D.A.; Testa, J.R. Perturbations of the AKT signaling pathway in human cancer. Oncogene, 2005, 24(50), 7455-7464. Available From: https://www.nature.com/articles/1209085
[http://dx.doi.org/10.1038/sj.onc.1209085] [PMID: 16288292]
[14]
Stambolic, V.; Woodgett, J.R. Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol., 2006, 16(9), 461-466. Available From: https://www.sciencedirect.com/science/article/pii/S0962892406001735
[http://dx.doi.org/10.1016/j.tcb.2006.07.001] [PMID: 16870447]
[15]
Whiteman, E.L.; Cho, H.; Birnbaum, M.J. Role of Akt/protein kinase B in metabolism. Trends Endocrinol. Metab., 2002, 13(10), 444-451. Available From: https://www.sciencedirect.com/science/article/pii/S1043276002006628
[http://dx.doi.org/10.1016/S1043-2760(02)00662-8] [PMID: 12431841]
[16]
Khezri, M.R.; Varzandeh, R.; Ghasemnejad-Berenji, M. The probable role and therapeutic potential of the PI3K/AKT signaling pathway in SARS-CoV-2 induced coagulopathy. Cellular and Molecular Biology Letters. BioMed Central Ltd, 2022; Vol. 27, .
[17]
Brognard, J.; Clark, A.S.; Ni, Y.; Dennis, P.A. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res., 2001, 61(10), 3986-3997. Available From: https://cancerres.aacrjournals.org/content/61/10/3986.short [Internet].
[PMID: 11358816]
[18]
Hemmings, B.A.; Restuccia, D.F. PI3K-PKB/Akt pathway. Cold Spring Harb. Perspect. Biol., 2012, 4(9), a011189. Available From: https://cshperspectives.cshlp.org/content/4/9/a011189.short
[http://dx.doi.org/10.1101/cshperspect.a011189] [PMID: 22952397]
[19]
Pal, S.K.; Reckamp, K.; Yu, H.; Figlin, R.A. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin. Investig. Drugs, 2010, 19(11), 1355-1366.
[http://dx.doi.org/10.1517/13543784.2010.520701] [PMID: 20846000]
[20]
Guo, T.; Liu, D.F.; Peng, S.H.; Abid, H. CDK9 is up-regulated and associated with prognosis in patients with papillary thyroid carcinom. Medicine (United States, 2022, 101(5), E28309. Available From: https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8812708/ accessed on 2022 May 19
[21]
Olson, C.M.; Jiang, B.; Erb, M.A.; Liang, Y.; Doctor, Z.M.; Zhang, Z.; Zhang, T.; Kwiatkowski, N.; Boukhali, M.; Green, J.L.; Haas, W.; Nomanbhoy, T.; Fischer, E.S.; Young, R.A.; Bradner, J.E.; Winter, G.E.; Gray, N.S. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat. Chem. Biol., 2018, 14(2), 163-170. Available From: https://www.nature.com/articles/nchembio.2538
[http://dx.doi.org/10.1038/nchembio.2538] [PMID: 29251720]
[22]
Morales, F.; Giordano, A. Overview of CDK9 as a target in cancer research. Cell Cycle. Taylor and Francis Inc, 2016, 15, 519-27. Available From: https://www.tandfonline.com/doi/abs/10.1080/15384101.2016.1138186 accessed on 2022 May 19
[23]
Egloff, S. CDK9 keeps RNA polymerase II on track. Cellular and Molecular Life Sciences. Springer Science and Business Media Deutschland GmbH, 2021; 78, pp. 5543-5567.
[24]
Hochegger, H.; Takeda, S.; Hunt, T. Cyclin-dependent kinases and cell-cycle transitions: Does one fit all? Nat. Rev. Mol. Cell Biol., 2008, 9(11), 910-916. Available From: https://www.nature.com/articles/nrm2510
[http://dx.doi.org/10.1038/nrm2510] [PMID: 18813291]
[25]
Borowczak, J.; Szczerbowski, K.; Ahmadi, N.; Szylberg, Ł. CDK9 inhibitors in multiple myeloma: A review of progress and perspectives. Med. Oncol., 2022, 39(4), 39. Available From: https://link.springer.com/article/10.1007/s12032-021-01636-1
[http://dx.doi.org/10.1007/s12032-021-01636-1] [PMID: 35092513]
[26]
Malumbres, M. Cyclin-dependent kinases. Genome Biol., 2014, 15(6), 122.
[http://dx.doi.org/10.1186/gb4184] [PMID: 25180339]
[27]
Shore, S.M.; Byers, S.A.; Dent, P.; Price, D.H. Characterization of Cdk955 and differential regulation of two Cdk9 isoforms. Gene, 2005, 350(1), 51-58. Available From: https://www.sciencedirect.com/science/article/pii/S0378111905000430
[http://dx.doi.org/10.1016/j.gene.2005.01.015] [PMID: 15780980]
[28]
Liu, H.; Herrmann, C.H. Differential localization and expression of the Cdk9 42k and 55k isoforms. J. Cell. Physiol., 2005, 203(1), 251-260.
[http://dx.doi.org/10.1002/jcp.20224] [PMID: 15452830]
[29]
Baumli, S.; Lolli, G.; Lowe, E.D.; Troiani, S.; Rusconi, L.; Bullock, A.N.; Debreczeni, J.É.; Knapp, S.; Johnson, L.N. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J., 2008, 27(13), 1907-1918.
[http://dx.doi.org/10.1038/emboj.2008.121] [PMID: 18566585]
[30]
Borowczak, J.; Szczerbowski, K.; Maniewski, M.; Zdrenka, M.; Słupski, P.; Antosik, P.; Kołodziejska, S.; Sekielska-Domanowska, M.; Dubiel, M.; Bodnar, M.; Szylberg, Ł. The prognostic role of cdk9 in bladder cancer. Cancers, 2022, 14(6), 1492. Available From: https://www.mdpi.com/2072-6694/14/6/1492
[http://dx.doi.org/10.3390/cancers14061492] [PMID: 35326643]
[31]
Beauchamp, E.M.; Abedin, S.M.; Radecki, S.G.; Fischietti, M.; Arslan, ADi.; Blyth, GT. Identification and targeting of novel CDK9 complexes in acute myeloid leukemia. Blood, 2019. Available From: https://ashpublications.org/blood/article-abstract/133/11/1171/260506 accessed on 2022 May 17
[32]
Fiskus, W.; Manshouri, T.; Birdwell, C.; Mill, C.P.; Masarova, L.; Bose, P. Efficacy of CDK9 inhibition in therapy of post-myeloproliferative neoplasm (MPN) secondary (s) AML cells. Blood Cancer Journal, 2022, 12 Available From: https://www.nature.com/articles/s41408-022-00618-4 accessed on 2022 May 19
[33]
Abudureheman, T.; Xia, J.; Li, M.H.; Zhou, H.; Zheng, W.W.; Zhou, N.; Shi, R.Y.; Zhu, J.M.; Yang, L.T.; Chen, L.; Zheng, L.; Xue, K.; Qing, K.; Duan, C.W. CDK7 Inhibitor thz1 induces the cell apoptosis of b-cell acute lymphocytic leukemia by perturbing cellular metabolism. Front. Oncol., 2021, 11, 663360.
[http://dx.doi.org/10.3389/fonc.2021.663360] [PMID: 33889549]
[34]
Ferri, M.; Liscio, P.; Carotti, A.; Asciutti, S.; Sardella, R.; Macchiarulo, A.; Camaioni, E. Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors. Eur. J. Med. Chem., 2017, 142, 506-522. Available From: https://www.sciencedirect.com/science/article/pii/S0223523417307444
[http://dx.doi.org/10.1016/j.ejmech.2017.09.030] [PMID: 29107427]
[35]
Verma, A.; Kumar, A.; Chugh, A.; Kumar, S.; Kumar, P. Tankyrase inhibitors: Emerging and promising therapeutics for cancer treatment. Medicinal Chemistry Research, 2020, 30(1), 50-73. Available From: https://link.springer.com/article/10.1007/s00044-020-02657-7 accessed on 2021 Aug 19
[36]
Peters, X.Q.; Malinga, T.H.; Agoni, C.; Olotu, F.A.; Soliman, M.E.S. Zoning in on tankyrases: A brief review on the past, present and prospective studies. Anticancer. Agents Med. Chem., 2020, 19(16), 1920-1934.
[http://dx.doi.org/10.2174/1871520619666191019114321] [PMID: 31648650]
[37]
Shirai, F.; Tsumura, T.; Yashiroda, Y.; Yuki, H.; Niwa, H.; Sato, S.; Chikada, T.; Koda, Y.; Washizuka, K.; Yoshimoto, N.; Abe, M.; Onuki, T.; Mazaki, Y.; Hirama, C.; Fukami, T.; Watanabe, H.; Honma, T.; Umehara, T.; Shirouzu, M.; Okue, M.; Kano, Y.; Watanabe, T.; Kitamura, K.; Shitara, E.; Muramatsu, Y.; Yoshida, H.; Mizutani, A.; Seimiya, H.; Yoshida, M.; Koyama, H. Discovery of novel spiroindoline derivatives as selective tankyrase inhibitors. J. Med. Chem., 2019, 62(7), 3407-3427.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01888] [PMID: 30883102]
[38]
Mygland, L.; Brinch, S.A.; Strand, M.F.; Olsen, P.A.; Aizenshtadt, A.; Lund, K.; Solberg, N.T.; Lycke, M.; Thorvaldsen, T.E.; Espada, S.; Misaghian, D.; Page, C.M.; Agafonov, O.; Nygård, S.; Chi, N.W.; Lin, E.; Tan, J.; Yu, Y.; Costa, M.; Krauss, S.; Waaler, J. Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines. iScience, 2021, 24(7), 102807. Available From: https://www.sciencedirect.com/science/article/pii/S2589004221007756
[http://dx.doi.org/10.1016/j.isci.2021.102807] [PMID: 34337362]
[39]
Peters, X.Q.; Agoni, C.; Soliman, M.E.S. Unravelling the structural mechanism of action of 5-methyl-5-[4-(4-oxo-3h-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione in dual-targeting tankyrase 1 and 2: A novel avenue in cancer therapy. Cell Biochemistry and Biophysics, 2022, 1-14. Available From: https://link.springer.com/article/10.1007/s12013-022-01076-2 accessed on 2022 Jun 6
[40]
Haikarainen, T.; Krauss, S.; Lehtio, L. Tankyrases: Structure, function and therapeutic implications in cancer. Curr. Pharm. Des., 2014, 20(41), 6472-6488.
[http://dx.doi.org/10.2174/1381612820666140630101525] [PMID: 24975604]
[41]
Mariotti, L.; Templeton, C.M.; Ranes, M.; Paracuellos, P.; Cronin, N.; Beuron, F.; Morris, E.; Guettler, S. Tankyrase requires SAM domain-dependent polymerization to support Wnt-β-catenin signaling. Mol. Cell, 2016, 63(3), 498-513.
[http://dx.doi.org/10.1016/j.molcel.2016.06.019] [PMID: 27494558]
[42]
Lehtiö, L.; Collins, R.; van den Berg, S.; Johansson, A.; Dahlgren, L.G.; Hammarström, M.; Helleday, T.; Holmberg-Schiavone, L.; Karlberg, T.; Weigelt, J. Zinc binding catalytic domain of human tankyrase 1. J. Mol. Biol., 2008, 379(1), 136-145.
[http://dx.doi.org/10.1016/j.jmb.2008.03.058] [PMID: 18436240]
[43]
Haikarainen, T.; Koivunen, J.; Narwal, M.; Venkannagari, H.; Obaji, E.; Joensuu, P.; Pihlajaniemi, T.; Lehtiö, L. para-Substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors. ChemMedChem, 2013, 8(12), 1978-1985.
[http://dx.doi.org/10.1002/cmdc.201300337] [PMID: 24130191]
[44]
De Rycker, M.; Price, C.M. Tankyrase polymerization is controlled by its sterile alpha motif and poly(ADP-ribose) polymerase domains. Mol. Cell. Biol., 2004, 24(22), 9802-9812.
[http://dx.doi.org/10.1128/MCB.24.22.9802-9812.2004] [PMID: 15509784]
[45]
Zamudio-Martinez, E; Herrera-Campos, AB; Muñoz, A; Rodríguez-Vargas, JM; Oliver, FJ Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities. J. Exp. Clin. Cancer Res. BioMed Central Ltd, 2021, 1-15.
[http://dx.doi.org/10.1186/s13046-021-01950-6]
[46]
Villegas, I.; Sanchez-Fidalgo, S.; Sánchez-Fidalgo, S.; Alarcon de la Lastra, C.; Villegas, I.; Sanchez-Fidalgo, S. Poly(ADP-ribose) polymerase inhibitors: New pharmacological functions and potential clinical implications. Curr. Pharm. Des., 2007, 13(9), 933-962.
[http://dx.doi.org/10.2174/138161207780414241] [PMID: 17430191]
[47]
Menon, M.; Elliott, R.; Bowers, L.; Balan, N.; Rafiq, R.; Costa-Cabral, S.; Munkonge, F.; Trinidade, I.; Porter, R.; Campbell, A.D.; Johnson, E.R.; Esdar, C.; Buchstaller, H.P.; Leuthner, B.; Rohdich, F.; Schneider, R.; Sansom, O.; Wienke, D.; Ashworth, A.; Lord, C.J. A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors. Sci. Rep., 2019, 9(1), 201.
[http://dx.doi.org/10.1038/s41598-018-36447-4] [PMID: 30655555]
[48]
Park, H.W.; Guan, K.L. Regulation of the Hippo pathway and implications for anticancer drug development. Trends Pharmacol. Sci., 2013, 34(10), 581-589.
[http://dx.doi.org/10.1016/j.tips.2013.08.006] [PMID: 24051213]
[49]
Wang 2015. Tankyrase inhibitors target YAP by stabilizing angiomotin family proteins. Physiol. Behav., 2018, 176(5), 139-148.
[50]
Kierulf-Vieira, K.S.; Sandberg, C.J.; Waaler, J.; Lund, K.; Skaga, E.; Saberniak, B.M.; Panagopoulos, I.; Brandal, P.; Krauss, S.; Langmoen, I.A.; Vik-Mo, E.O. A small-molecule tankyrase inhibitor reduces glioma stem cell proliferation and sphere formation. Cancers, 2020, 12(6), 1630.
[http://dx.doi.org/10.3390/cancers12061630] [PMID: 32575464]
[51]
Nkizinkiko, Y.; Desantis, J.; Koivunen, J.; Haikarainen, T.; Murthy, S.; Sancineto, L.; Massari, S.; Ianni, F.; Obaji, E.; Loza, M.I.; Pihlajaniemi, T.; Brea, J.; Tabarrini, O.; Lehtiö, L. 2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors. Sci. Rep., 2018, 8(1), 1680.
[http://dx.doi.org/10.1038/s41598-018-19872-3] [PMID: 29374194]
[52]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation.Cell Press, 2011, pp. 646-674.
[53]
Fares, J.; Fares, M.Y.; Khachfe, H.H.; Salhab, H.A.; Fares, Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduction and Targeted Therapy, 2020, 5 Available From: https://www.nature.com/articles/s41392-020-0134-x accessed on 2022 May 16
[54]
Yard, B.D.; Adams, D.J.; Chie, E.K.; Tamayo, P.; Battaglia, J.S.; Gopal, P.; Rogacki, K.; Pearson, B.E.; Phillips, J.; Raymond, D.P.; Pennell, N.A.; Almeida, F.; Cheah, J.H.; Clemons, P.A.; Shamji, A.; Peacock, C.D.; Schreiber, S.L.; Hammerman, P.S.; Abazeed, M.E. A genetic basis for the variation in the vulnerability of cancer to DNA damage. Nat. Commun., 2016, 7(1), 11428. Available From: https://www.nature.com/articles/ncomms11428
[http://dx.doi.org/10.1038/ncomms11428] [PMID: 27109210]
[55]
Schaue, D.; McBride, W.H. Opportunities and challenges of radiotherapy for treating cancer. Nat. Rev. Clin. Oncol., 2015, 12(9), 527-540. Available From: https://www.nature.com/articles/nrclinonc.2015.120
[http://dx.doi.org/10.1038/nrclinonc.2015.120] [PMID: 26122185]
[56]
Lawrence, T.S.; Haffty, B.G.; Harris, J.R. Milestones in the use of combined-modality radiation therapy and chemotherapy. J. Clin. Oncol., 2014, 32(12), 1173-1179.
[http://dx.doi.org/10.1200/JCO.2014.55.2281] [PMID: 24663053]
[57]
Burley, S.K.; Berman, H.M.; Christie, C.; Duarte, J.M.; Feng, Z.; Westbrook, J.; Young, J.; Zardecki, C. RCSB Protein Data Bank: Sustaining a living digital data resource that enables breakthroughs in scientific research and biomedical education. Protein Sci., 2018, 27(1), 316-330. Available From: https://onlinelibrary.wiley.com/doi/full/10.1002/pro.3331
[http://dx.doi.org/10.1002/pro.3331] [PMID: 29067736]
[58]
Berman, H.M.; Battistuz, T.; Bhat, T.N.; Bluhm, W.F.; Bourne, P.E.; Burkhardt, K. TheProtein Data Bank, 2002, 58(6-1), 899-907. Internet Available From: https://www.onlinelibrary.wiley.com/doi/abs/10.1107/S0907444902003451
[59]
Kusumaningrum, S.; Budianto, E.; Kosela, S.; Sumaryono, W.; Juniarti, F. The molecular docking of 1,4-naphthoquinone derivatives as inhibitors of Polo-like kinase 1 using Molegro Virtual Docker. J. Appl. Pharm. Sci., 2014, 4(11), 47-53. Available From: http://www.academia.edu/download/54300101/The_molecular_docking_of_14-naphthoquino20170831-2707-1eyf3nf.pdf [Internet].
[60]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera?A visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612. Available From: https://pubmed.ncbi.nlm.nih.gov/15264254/
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[61]
Eswar, N.; Webb, B.; Marti-Renom, M.A.; Madhusudhan, M.S.; Eramian, D.; Shen, M.Y.; Pieper, U.; Sali, A. Comparative protein structure modeling using Modeller. Curr. Protoc. Bioinformatics, 2006, Chapter 5(1), 6.
[PMID: 18428767]
[62]
Cherinka, B.; Andrews, B.H.; Sánchez-Gallego, J.; Brownstein, J.; Argudo-Fernández, M.; Blanton, M.; Bundy, K.; Jones, A.; Masters, K.; Law, D.R.; Rowlands, K.; Weijmans, A-M.; Westfall, K.; Yan, R. Marvin: A tool kit for streamlined access and visualization of the SDSS-IV manga data set. Astron. J., 2019, 158(2), 74. Available From: https://ui.adsabs.harvard.edu/abs/2019AJ....158...74C/abstract [Internet].
[http://dx.doi.org/10.3847/1538-3881/ab2634]
[63]
ChemAxon. Marvin | ChemAxon. 2020. Available From: https://chemaxon.com/products/marvin accessed on 2022 Mar 22
[64]
Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform., 2012, 4(1), 17.
[http://dx.doi.org/10.1186/1758-2946-4-17] [PMID: 22889332]
[65]
Salifu, E.Y.; Issahaku, A.R.; Agoni, C.; Ibrahim, M.A.A.; Manimbulu, N.; Soliman, M.E.S. Prioritizing the catalytic gatekeepers through pan- inhibitory mechanism of entrectinib against ALK, ROS1 and TRKA tyrosine kinases. Cell Biochem. Biophys., 2022, 80(1), 11-21.
[http://dx.doi.org/10.1007/s12013-021-01052-2] [PMID: 35040089]
[66]
Trott, O; Olson, AJ AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2009.
[67]
Eberhardt, J.; Santos-Martins, D.; Tillack, A.F.; Forli, S. Autodock vina 1.2.0: New docking methods, expanded force field, and python bindings. J. Chem. Inf. Model., 2021, 61(8), 3891-3898.
[http://dx.doi.org/10.1021/acs.jcim.1c00203] [PMID: 34278794]
[68]
Case, D.A.; Ben-Shalom, I.Y.; Brozell, S.R.; Cerutti, D.S.; Cheatham, T.E., III; Cruzeiro, V.W.D. Amber. University of California: San Francisco, 2018; p. 1. [Internet] Available From: http://ambermd.org/
[69]
Salomon-Ferrer, R.; Case, D.A.; Walker, R.C. An overview of the Amber biomolecular simulation package. Wiley Interdiscip. Rev. Comput. Mol. Sci., 2013, 3(2), 198-210. Available From: https://onlinelibrary.wiley.com/doi/pdf/10.1002/wcms.1121 [Internet].
[http://dx.doi.org/10.1002/wcms.1121]
[70]
Ponder, J.W.; Case, D.A. Force fields for protein simulations Elsevier., 2003. Available From: https://www.sciencedirect.com/science/article/pii/S006532330366002X accessed on 2020 Mar 31
[71]
Wang, J.; Wolf, R.M.; Caldwell, J.W.; Kollman, P.A.; Case, D.A. Development and testing of a general amber force field. J. Comput. Chem., 2004, 25(9), 1157-1174.
[http://dx.doi.org/10.1002/jcc.20035] [PMID: 15116359]
[72]
Grest, G.S.; Kremer, K. Molecular dynamics simulation for polymers in the presence of a heat bath. Phys. Rev. A Gen. Phys., 1986, 33(5), 3628-3631.
[http://dx.doi.org/10.1103/PhysRevA.33.3628] [PMID: 9897103]
[73]
Berendsen, H.J.C.; Postma, J.P.M.; van Gunsteren, W.F.; DiNola, A.; Haak, J.R. Molecular dynamics with coupling to an external bath. J. Chem. Phys., 1984, 81(8), 3684-3690. Available From: http://aip.scitation.org/doi/10.1063/1.448118 [Internet].
[http://dx.doi.org/10.1063/1.448118]
[74]
Omolabi, K.F.; Agoni, C.; Olotu, F.A.; Soliman, M.E.S. ‘Finding the needle in the haystack’- will natural products fit for purpose in the treatment of cryptosporidiosis? – A theoretical perspective. Mol. Simul., 2021, 47(8), 636-649.
[http://dx.doi.org/10.1080/08927022.2021.1895435]
[75]
Roe, D.R.; Cheatham, T.E., III PTRAJ and CPPTRAJ: Software for processing and analysis of molecular synamics trajectory data. J. Chem. Theory Comput., 2013, 9(7), 3084-3095.
[http://dx.doi.org/10.1021/ct400341p] [PMID: 26583988]
[76]
Seifert, E. OriginPro 9.1: Scientific data analysis and graphing software - Software review. J. Chem. Inf. Model. American Chemical Society, 2014, 54, 1552.
[77]
Hess, B.; Bekker, H.; Berendsen, H.J.C.; Fraaije, J.G.E.M. LINCS: A linear constraint solver for molecular simulations. Comput Chem. John Wiley & Sons, Inc, 1997. Available From: https://onlinelibrary.wiley.com/doi/abs/10.1002/(SICI)1096-987X(199709)18:12%3C1463:AID-JCC4%3E3.0.CO;2-H accessed on 2020 Mar 31
[78]
BIOVIA DS. Discovery Studio 2016 Client. San Diego: Dassault Systèmes. 2016. Available From: https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=D.+S.+BIOVIA%2C+ accessed on 2022 Mar 23
[79]
Massova, I.; Kollman, P.A. Combined molecular mechanical and continuum solvent approach (MM- PBSA/GBSA) to predict ligand binding. Vol. 18. Perspect. Drug Discov. Des., 2000, 18(1), 113-135.
[http://dx.doi.org/10.1023/A:1008763014207]
[80]
Genheden, S.; Kuhn, O.; Mikulskis, P.; Hoffmann, D.; Ryde, U. The normal-mode entropy in the MM/GBSA method: effect of system truncation, buffer region, and dielectric constant. J. Chem. Inf. Model., 2012, 52(8), 2079-2088.
[http://dx.doi.org/10.1021/ci3001919] [PMID: 22817270]
[81]
Onufriev, A.; Bashford, D.; Case, D.A. Modification of the generalized born model suitable for macromolecules. J. Phys. Chem. B, 2000, 104(15), 3712-3720. Available From: https://pubs.acs.org/doi/abs/10.1021/jp994072s [Internet].
[http://dx.doi.org/10.1021/jp994072s]
[82]
Ylilauri, M.; Pentikäinen, O.T. MMGBSA as a tool to understand the binding affinities of filamin-peptide interactions. J. Chem. Inf. Model., 2013, 53(10), 2626-2633.
[http://dx.doi.org/10.1021/ci4002475] [PMID: 23988151]
[83]
Kollman, P.A.; Massova, I.; Reyes, C.; Kuhn, B.; Huo, S.; Chong, L.; Lee, M.; Lee, T.; Duan, Y.; Wang, W.; Donini, O.; Cieplak, P.; Srinivasan, J.; Case, D.A.; Cheatham, T.E., III Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models. Acc. Chem. Res., 2000, 33(12), 889-897.
[http://dx.doi.org/10.1021/ar000033j] [PMID: 11123888]
[84]
Hou, T.; Wang, J.; Li, Y.; Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J. Chem. Inf. Model., 2011, 51(1), 69-82.
[http://dx.doi.org/10.1021/ci100275a] [PMID: 21117705]
[85]
Homeyer, N.; Gohlke, H. Free energy calculations by the molecular mechanics poisson−boltzmann surface area method. Mol. Inform., 2012, 31(2), 114-122. Available From: https://onlinelibrary.wiley.com/doi/abs/10.1002/minf.201100135
[http://dx.doi.org/10.1002/minf.201100135] [PMID: 27476956]
[86]
Sitkoff, D.; Sharp, K.A.; Honig, B. Accurate calculation of hydration free energies using macroscopic solvent models. J. Phys. Chem., 1994, 98(7), 1978-1988.
[http://dx.doi.org/10.1021/j100058a043]
[87]
Webborn, P.J.H. The role of pharmacokinetic studies in drug discovery: Where are we now, how did we get here and where are we going? Future Medicinal Chemistry. Future Science, 2014; Vol. 6, pp. 1233-1235.
[88]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[89]
Daina, A.; Zoete, V. A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem, 2016, 11(11), 1117-1121. Available From: https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.201600182
[http://dx.doi.org/10.1002/cmdc.201600182] [PMID: 27218427]
[90]
Elamin, G.; Aljoundi, A.; Alahmdi, M.I.; Abo-Dya, N.E.; Soliman, M.E.S. Battling BTK mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations in Waldenström macroglobulinemia therapy: Structural mechanistic insights on the role of fenebrutinib. J. Mol. Model., 2022, 28(11), 355. Available From: https://link.springer.com/article/10.1007/s00894-022-05345-y
[http://dx.doi.org/10.1007/s00894-022-05345-y] [PMID: 36222928]
[91]
Ahmed, S.S.S.J.; Ramakrishnan, V. Systems biological approach of molecular descriptors connectivity: Optimal descriptors for oral bioavailability prediction. PLoS One, 2012, 7(7), e40654.
[http://dx.doi.org/10.1371/journal.pone.0040654] [PMID: 22815781]
[92]
Mukherjee, J.; Gupta, M.N. Increasing importance of protein flexibility in designing biocatalytic processes. Biotechnol. Rep., 2015, 6, 119-123. Available From: https://www.sciencedirect.com/science/article/pii/S2215017X1500020X
[http://dx.doi.org/10.1016/j.btre.2015.04.001] [PMID: 28626705]
[93]
Xie, Y.; An, J.; Yang, G.; Wu, G.; Zhang, Y.; Cui, L.; Feng, Y. Enhanced enzyme kinetic stability by increasing rigidity within the active site. J. Biol. Chem., 2014, 289(11), 7994-8006. Available From: https://www.jbc.org/article/S0021-9258(20)44301-7/abstract
[http://dx.doi.org/10.1074/jbc.M113.536045] [PMID: 24448805]
[94]
Celej, M.S.; Montich, G.G.; Fidelio, G.D. Protein stability induced by ligand binding correlates with changes in protein flexibility. Protein Sci., 2003, 12(7), 1496-1506. Available From: https://onlinelibrary.wiley.com/doi/abs/10.1110/ps.0240003
[http://dx.doi.org/10.1110/ps.0240003] [PMID: 12824495]
[95]
Liu, K.; Watanabe, E.; Kokubo, H. Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations. J. Comput. Aided Mol. Des., 2017, 31(2), 201-211.
[http://dx.doi.org/10.1007/s10822-016-0005-2] [PMID: 28074360]
[96]
Agoni, C.; Salifu, E.Y.; Munsamy, G.; Olotu, F.A.; Soliman, M. CF 3 ‐Pyridinyl substitution on antimalarial therapeutics: probing differential ligand binding and dynamical inhibitory effects of a novel triazolopyrimidine‐based inhibitor on Plasmodium falciparum dihydroorotate dehydrogenase. Chem. Biodivers., 2019, 16(12), e1900365.
[http://dx.doi.org/10.1002/cbdv.201900365] [PMID: 31589372]
[97]
Luque, I.; Freire, E.; Saecker, R.M.; Record, M.T. Structural stability of binding sites: Consequences for binding affinity and allosteric effects. Proteins, 2000, 41(S4)(Suppl. 4), 63-71. Available From: https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0134(2000)41:4+%3C63:AID-PROT60%3E3.0.CO;2-6
[http://dx.doi.org/10.1002/1097-0134(2000)41:4+<63::AID-PROT60>3.0.CO;2-6] [PMID: 11013401]
[98]
Brüschweiler, R. Efficient RMSD measures for the comparison of two molecular ensembles. Proteins, 2003, 50(1), 26-34.
[http://dx.doi.org/10.1002/prot.10250] [PMID: 12471596]
[99]
Pitera, J.W. Expected distributions of root-mean-square positional deviations in proteins. J. Phys. Chem. B, 2014, 118(24), 6526-6530. Available From: https://pubs.acs.org/doi/abs/10.1021/jp412776d
[http://dx.doi.org/10.1021/jp412776d] [PMID: 24655018]
[100]
Kumar, CV; Swetha, RG; Anbarasu, A; Ramaiah, S Computational analysis reveals the association of threonine 118 methionine mutation in PMP22 resulting in CMT-1A. Advances in Bioinformatics, 2014.
[http://dx.doi.org/10.1155/2014/502618]
[101]
Teilum, K.; Olsen, J.G.; Kragelund, B.B. Functional aspects of protein flexibility. Cell. Mol. Life Sci., 2009, 66(14), 2231-2247. Available From: https://link.springer.com/article/10.1007/s00018-009-0014-6
[http://dx.doi.org/10.1007/s00018-009-0014-6] [PMID: 19308324]
[102]
Gromiha, M.; Ahmad, S. Role of solvent accessibility in structure based drug design. Curr. Computeraided Drug Des., 2005, 1(3), 223-235. Available From: https://www.ingentaconnect.com/content/ben/cad/2005/00000001/00000003/art00001 [Internet].
[http://dx.doi.org/10.2174/1573409054367664]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version337msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[08:36:01] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[08:36:01] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[08:36:01] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[08:36:01] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (126ms)time
  • Application (211ms)time
  • 1 x Application (62.73%)
    211ms
    1 x Booting (37.27%)
    126ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    36 statements were executed, 4 of which were duplicates, 32 unique. Show only duplicated116ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('314340157','',1,1740472561,1740472561) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740472561
      1.3msalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('314340157','/article/133609',1,1740472561,1740472561)
      240μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 314340157 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314340157) limit 1
      12.85msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 314340157
      • 1: 314340157
      • 2: 314340157
      • 3: 314340157
      • 4: 314340157
      • 5: 314340157
      • 6: 314340157
      • 7: 314340157
      • 8: 314340157
      • 9: 314340157
      • 10: 314340157
      • 11: 314340157
      • 12: 314340157
      • 13: 314340157
      • 14: 314340157
      • 15: 314340157
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • SELECT at.type_name, p.copyright, p.publisher_location,m.month,y.year, a.publish_on, a.nid article_nid,a.article_id, a.pmid, a.issue_id, a.title, a.abstract,a.podcast,a.altmetric_score,a.altmetric_url,a.kudos_url, a.page_count, a.first_page, a.elocator, a.last_page, i.publication_date, a.file_name, a.file_path, a.doi, a.is_epub,a.epub_type, a.volume_id, a.is_uploaded, a.editor_choice, a.is_epub, j.image_file_name, a.article_no, a.art_type AS article_type, a.supplementary_filename,a.html_filename,a.prc_filename,a.epub_filename, a.graph_abs_lg_filename, a.graph_abs_sm_filename, a.oa_image_lg_filename, a.oa_image_sm_filename, j.journal_banner,a.animated_abstract,a.erratum_in,a.erratum_for, (CASE WHEN a.issue_id =0 THEN j.epub_price ELSE j.price END) AS sell_price, j.epub_price, j.nid AS jour_nid, j.title AS journal_title, j.issn, j.eissn,j.journal_id, j.subtitle AS jour_subtitle, v.volume_id,v.volume_name AS volume, v.year_id, i.title AS issue, i.month_id ,i.type issue_type, j.subtitle,j.formerly_title, ac.subtitle AS epub_title,a.crossmark_enabled,a.text_mining_urls,a.license_urls,a.created, a.receivedate, a.revisedate, a.acceptdate,js.js_title FROM article a LEFT JOIN article_section ac ON a.is_epub = ac.art_sec_id LEFT JOIN journal_section js ON a.js_id = js.js_id LEFT JOIN article_type at ON a.art_type = at.art_type_id LEFT JOIN issue i ON a.issue_id = i.issue_id LEFT JOIN month m ON m.id = i.month_id LEFT JOIN volume v ON v.volume_id = a.volume_id INNER JOIN year y ON y.id = v.year_id INNER JOIN journal j ON j.journal_id = a.journal_id INNER JOIN publisher p ON p.publisher_id = j.publisher_id WHERE a.article_id=133609
      960μsalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 30 limit 1
      1.2msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 30
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=30) and sj.journal_id!=30 group by `j`.`nid`) as `aggregate_table`
      1.13msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=30) and sj.journal_id!=30 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      920μsalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=30) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.55msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=30) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.35msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '133609'
      220μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 133609
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '133609'
      4msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 133609
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '133609' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.67msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 133609
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      240μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      460μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 30 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      34.65msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 30 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      12.78msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 30 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      10.46msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 133609 limit 1
      320μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 133609
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 133609 and content_type = 'article' order by status desc limit 1
      370μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 219735 limit 1
      230μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 219735
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      260μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CPB' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      340μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CPB
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '133609' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      400μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '13257' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      360μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '3454' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      320μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3454) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3454) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3454)
      15.76msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13257) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13257) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13257)
      770μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 133609) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 133609) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314340157 and j.to_ip >=314340157 )) and ((j.from_date <= 1740472561 and j.to_date >= 1740472561 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 133609)
      630μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '1288' and is_uploaded = 1 and issue_id = 13257 order by cast(first_page as SIGNED) desc limit 1
      590μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1288
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '1303' and is_uploaded = 1 and issue_id = 13257 order by cast(first_page as SIGNED) asc limit 1
      510μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1303
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      200μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      230μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 133609 limit 1
      3.94msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 133609
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 30 and `b`.`banner_from_date` <= 1740472561 and `b`.`banner_to_date` >= 1740472561 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.64msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 30
      • 3: 1740472561
      • 4: 1740472561
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 30 and `b`.`banner_from_date` <= 1740472561 and `b`.`banner_to_date` >= 1740472561 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.6msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 30
      • 3: 1740472561
      • 4: 1740472561
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='5233ecb07bb3832a294679e92a71bfdb'
      300μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        TiVce6BYxSXAnKfU9cvw9NY3FllyhGdoZ4D2fVnx
        uc_cart_id
        5233ecb07bb3832a294679e92a71bfdb
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/133609" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/133609
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6Ik93WjlqUG9saElidlFiSUJ5MGRCUEE9PSIsInZhbHVlIjoibVE3VDAvNC9yOVdwQ2dHMEdHRWE2SHBRTTBQNXVWWkpzQjlPMDZ0L1g2UT0iLCJtYWMiOiJjOTBlZGQxNjVjMWZlODJjNjBjNWIzYjAwZDUwNTcxYWU0MTZlZmZmZjI5ZDBkZGM5ODcxMTA4ODg2OTBhZWY2IiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6Ik93WjlqUG9saElidlFiSUJ5MGRCUEE9PSIsInZhbHVlIjoibVE3VDAvNC9yOVdwQ2dHMEdHRWE2SHBRTTBQNXVWWkpzQjlPMDZ0L1g2UT0iLCJtYWMiOiJjOTBlZGQxNjVjMWZl" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 08:36:01 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjhnYmxtb3gzSDZHNkM2WmpvUWZFZ2c9PSIsInZhbHVlIjoiKzRMam4xVjk3akp6NEJpc0g5RDIvSVo5aDI5b21BcTZaNTBSQ0xHNGZVbmVaWnR2R1dpbmpFVUE4L1NYcmpEVDUyVXNiNDJpWmkwZm4zL3ErN3JXb0ZJRmlzTS9VemhTM05SemVRUitJTkZDTjFic2FMeG5rVGc1RUgvdGtPMFUiLCJtYWMiOiJiNTkyNDAxOTNhMTg3OWU0MzkyMmQzODllNTMxZjJhNDQ3ZDc0NWRhNDAzYTI3Y2IyOWQ1NGZkZTkzNjRjN2NhIiwidGFnIjoiIn0%3D; expires=Thu, 27 Feb 2025 20:36:01 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IjhnYmxtb3gzSDZHNkM2WmpvUWZFZ2c9PSIsInZhbHVlIjoiKzRMam4xVjk3akp6NEJpc0g5RDIvSVo5aDI5b21BcTZaNTBSQ0xHNGZVbmVaWnR2R1dpbmpFVUE4L1NYcmpEVDUyVXNiN" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkFUMkVQZmpOSFZzb1REN3RacnRGZ0E9PSIsInZhbHVlIjoiYzVkdmJ2TXdsaXFyczZaK2R5TTNqeVo3NFNqVmdBRWtKTlg5V0xTM0dIa1hFeFVrUzIyWVhVWGlJMVNVZWZIV3pKdTBJUFhjc3EwV0pZM1dBSWVkeThPZ21wMnNUQ1pMSk5rZGUwN3NVUXVLeXNOYjhOVm1Vb3RVeEpkVDh0c1YiLCJtYWMiOiI2YzYxYTdjZjI4MDcxZWI2MDNjOWIyZGFhOTFjMzE3NzUyZTc3NjJlZGQ2YWJjM2FkYjIzNDU5MWZlNDZkNjVlIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IkFUMkVQZmpOSFZzb1REN3RacnRGZ0E9PSIsInZhbHVlIjoiYzVkdmJ2TXdsaXFyczZaK2R5TTNqeVo3NFNqVmdBRWtKTlg5V0xTM0dIa1hFeFVrUzIyWVhVWGl" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjhnYmxtb3gzSDZHNkM2WmpvUWZFZ2c9PSIsInZhbHVlIjoiKzRMam4xVjk3akp6NEJpc0g5RDIvSVo5aDI5b21BcTZaNTBSQ0xHNGZVbmVaWnR2R1dpbmpFVUE4L1NYcmpEVDUyVXNiNDJpWmkwZm4zL3ErN3JXb0ZJRmlzTS9VemhTM05SemVRUitJTkZDTjFic2FMeG5rVGc1RUgvdGtPMFUiLCJtYWMiOiJiNTkyNDAxOTNhMTg3OWU0MzkyMmQzODllNTMxZjJhNDQ3ZDc0NWRhNDAzYTI3Y2IyOWQ1NGZkZTkzNjRjN2NhIiwidGFnIjoiIn0%3D; expires=Thu, 27-Feb-2025 20:36:01 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IjhnYmxtb3gzSDZHNkM2WmpvUWZFZ2c9PSIsInZhbHVlIjoiKzRMam4xVjk3akp6NEJpc0g5RDIvSVo5aDI5b21BcTZaNTBSQ0xHNGZVbmVaWnR2R1dpbmpFVUE4L1NYcmpEVDUyVXNiN" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkFUMkVQZmpOSFZzb1REN3RacnRGZ0E9PSIsInZhbHVlIjoiYzVkdmJ2TXdsaXFyczZaK2R5TTNqeVo3NFNqVmdBRWtKTlg5V0xTM0dIa1hFeFVrUzIyWVhVWGlJMVNVZWZIV3pKdTBJUFhjc3EwV0pZM1dBSWVkeThPZ21wMnNUQ1pMSk5rZGUwN3NVUXVLeXNOYjhOVm1Vb3RVeEpkVDh0c1YiLCJtYWMiOiI2YzYxYTdjZjI4MDcxZWI2MDNjOWIyZGFhOTFjMzE3NzUyZTc3NjJlZGQ2YWJjM2FkYjIzNDU5MWZlNDZkNjVlIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IkFUMkVQZmpOSFZzb1REN3RacnRGZ0E9PSIsInZhbHVlIjoiYzVkdmJ2TXdsaXFyczZaK2R5TTNqeVo3NFNqVmdBRWtKTlg5V0xTM0dIa1hFeFVrUzIyWVhVWGl" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "TiVce6BYxSXAnKfU9cvw9NY3FllyhGdoZ4D2fVnx" "uc_cart_id" => "5233ecb07bb3832a294679e92a71bfdb" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/133609" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 08:36:01GET/article/133609414361